Post-Translational Modifications That Drive Prostate Cancer Progression
Abstract
:1. Introduction
2. Post-Translational Modifications
3. Post-Translational Modifications in Prostate Cancer
3.1. Phosphorylation
3.2. Glycosylation
3.3. Ubiquitination
3.4. SUMOylation
3.5. Acetylation
3.6. Lipidation
4. Therapeutic Potential of Post-Translational Modifications in Prostate Cancer
5. Conclusions
Funding
Conflicts of Interest
References
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PTM | Experimental Setting | Main Findings | Ref. |
---|---|---|---|
Phosphorylation | Comparative phosphoproteomics of differentially expressed kinases between the highly aggressive PC-3 and PC-3M cells. | PAK2, SLK, MST4, MAP2K2, and ARAF are kinases that are potentially associated with increased migration in PC-3M cells. | [19] |
(Phospho)proteomic profiling of human prostate cancer (PCa)-associated fibroblasts. | PCa-associated fibroblasts-derived LOXL2 is an important mediator of intercellular communication within the prostate tumor microenvironment. | [20] | |
Characterization of the ERG-regulated kinome. | TNIK is suggested as a potential therapeutic target. | [21] | |
Phosphoproteome of treatment naive and metastatic CRPC tissue samples integrated with genomic and transcriptomic data. | Six major signaling pathways with phosphorylation of several key residues are significantly enriched in CRPC tumors; clinically relevant information (kinase target potential based on patient-specific networks) potentially suitable for patient stratification and targeted therapies in late stage PCa is provided. | [22] | |
Analysis of global phosphoproteomic changes induced by fish oil in human PCa. | Pyruvate dehydrogenase alpha 1 is a target of omega-3 polyunsaturated fatty acids in human PCa. | [23] | |
Phosphoproteomics data from mouse model of PCa progression [24] integrated with gene expression analysis and literature mining. | A total of 125 wild type kinases implicated in human PCa metastasis were selected for screen for in vivo metastatic ability; the RAF family, MERTK, and NTRK2 kinases drive PCa bone and visceral metastasis, and are highly expressed in human metastatic PCa tissues, potentially representing important therapeutic targets. | [25] | |
Comparative phosphoproteome analysis of a PCa cell line, LNCaP, and an LNCaP-derived androgen-independent cell line, LNCaP-AI. | The phosphorylation level of THRAP3 is significantly lower in LNCaP-AI cells; nonphosphorylatable mutant form of THRAP3 and the phosphorylation-mimic form differ significantly in protein binding repertoire; many of the differentially interacting proteins were identified as being involved in RNA splicing and processing. | [26] | |
Quantitative proteomic approach to compare protein phosphorylation in orthotopic xenograft tumors grown in either intact or castrated mice. | Changes in phosphorylation of YAP1 and PAK2 and their elevated levels in CRPC identified; YAP2 and PAK2 regulate cell colony formation and invasion in androgen-independent cells; PAK2 influences cell proliferation and mitotic timing; pharmacologic inhibitors of PAK2 and YAP1 are able to inhibit the growth of androgen-independent PC-3 xenografts. | [27] | |
Phosphotyrosine peptide enrichment and quantitative mass spectrometry (MS) in oncogene(non-TK)-driven mouse model of PCa progression. | Elevated TK signaling (EGFR, EPHA2, JAK2, ABL1, and steroid receptor coactivator (SRC) tyrosine kinase activation) is recorded. | [24] | |
Proteome analysis of Aurora-A substrates using small molecule inhibitor and reverse in-gel kinase assay in PC-3 cells. | NuMA becomes hypo-phosphorylated in vivo upon Aurora-A inhibition; mutation of three of these phospho-sites significantly diminishes cell proliferation and increases the rate of apoptosis; NuMA T1804A mutant mislocalizes to the cytoplasm in interphase nuclei in a punctate pattern. | [28] | |
Phosphoproteomics of metastatic docetaxel-resistant PCa cell lines (DU145-Rx and PC-3-Rx). | Increased phosphorylation of FAK mediates chemoresistance in CRPC. | [29] | |
Glycosylation | Proteomics analysis to determine the O-glycan profiles of PCa cells metastasized to bone (PC-3), brain (DU145), lymph node (LNCaP), and vertebra (VCaP) in comparison to immortalized RWPE-1 cells derived from normal prostatic tissue. | PCa cells exhibit an elevation of simple/short O-glycans, with a reduction of complex O-glycans, increased O-glycan sialylation, and decreased fucosylation. Core 1 sialylation is increased in all PCa cells. The expression of sialyl-3T antigen, which is the product of ST3Gal-I is increased. ST3Gal-I is associated with PC-3 cell proliferation, migration and apoptosis. Downregulation of ST3Gal-I reduces the tumor size in xenograft mouse model. | [30] |
Comprehensive proteomic approaches of FUT8 overexpressing PCa cells. | Upregulation of EGFR and its downstream signaling; increased cell survival in androgen-depleted conditions. | [31] | |
Extracellular vesicles (EV)-derived glycoproteins upon overexpression of FUT8 in PCa cells. | Reduced number of vesicles secreted by PCa cells; increase in the abundance of proteins associated with cell motility and PCa metastasis; altered glycans on select EV-derived glycoproteins. | [32] | |
O-GlcNAc chromatin consensus motif imposed by OGT used as a bait for MS; combination with MYC chromatin immunoprecipitation (ChIP)-MS in PCa cells. | OGT is an essential mediator in androgen-independency, which is the major mechanism of PCa progression. | [33] | |
Proteomics of androgen-dependent and androgen-resistant LAPC4 cells. | FUT8 is significantly overexpressed in the androgen-resistant LAPC4 cells; overexpression of FUT8 might be responsible for the decreased PSA expression in prostate cancer specimens. | [34] | |
Cell surface Thomsen–Friedenreich (TF) antigen proteome profiling of metastatic PCa cells. | CD44, α2 integrin, β1 integrin, CD49f, CD133, CD59, EphA2, CD138, transferrin receptor and profilin express TF antigen; TF antigen positive prostate cancer cells form significantly more and larger prostaspheres under both non-differentiating and differentiating conditions and express higher levels of stem cell markers. | [35] | |
Ubiquitination | Overexpression or depletion of USP22 in PCa cells and analysis of the ubiquitylome. | Depletion of USP22 sensitizes cells to genotoxic insult; analysis of the USP22-sensitive ubiquitylome identified the nucleotide excision repair protein, XPC, as a critical mediator of the USP22-mediated response to genotoxic insult. | [36] |
Knockdown of E6AP in DU145 cells and analysis of a proteome. | Clusterin is a novel target of E6AP; concomitant knockdown of clusterin and E6AP partially restores cell growth. | [37] | |
Changes in the ubiquitin landscape induced by prostate cancer–associated mutations of SPOP in immortalized prostate epithelial cells expressing endogenous SPOP. | DEK and TRIM24 are effector substrates consistently upregulated by SPOP mutants with decreases in ubiquitination and proteasomal degradation resulting from heteromeric complexes of wild type and mutant SPOP protein; DEK stabilization promotes prostate epithelial cell invasion. | [38] | |
SUMOylation | Quantitative proteomics to identify SUMOylated proteins in SUMO stably transfected PC-3 cells. | More than 900 putative target proteins of SUMO are identified; mutation of newly identified SUMO modification sites of USP39 further promotes the proliferation-enhancing effect of USP39 on PCa cells. | [39] |
Palmitoylation | Palmitoyl-proteomic analysis of large and small cancer-derived PCa EVs [40]. | STEAP1, STEAP2, and ABCC4 are identified as PCa-specific palmitoyl-proteins abundant in both EV populations; their localization in EVs is reduced upon inhibition of palmitoylation in the producing cells. | [40] |
Palmitoyl proteomic analysis of breast and PCa cell lines, ±DHHC3 ablation. | Putative substrates include 22–28 antioxidant/redox-regulatory proteins and DHHC3 ablation elevates oxidative stress; DHHC3 ablation, in combination with chemotherapeutic drug treatment, elevates oxidative stress, with a greater than additive effect, and enhances the anti-growth effects of the chemotherapeutic agents; DHHC3 ablation synergizes with PARP inhibitor PJ-34, to decrease cell proliferation and increase oxidative stress. | [41] | |
Proteomic experiments using clickable palmitate probe (Alk-C16) between three individual pairs of androgen-treated and non-treated LNCaP cells. | Androgen treatment significantly increased the palmitoylation level of eIF3L, which may be used as a biomarker for the diagnosis of early-stage PCa. | [42] | |
LNCaP cells metabolically-labeled with Alk-C16, a palmitate probe and treated with R1881, an androgen, or DMSO after which palmitoylome profiling was performed. | Androgen treatment significantly increases the palmitoylation level of α-tubulin and Ras-related protein Rab-7a (Rab7a), which are essential for cell proliferation; in the supernatant of LNCaP cells, the palmitoylation level of α-tubulin is also increased following androgen treatment, which may represent a biomarker for early-stage PCa. | [43] |
Sialylation O-linked glycans: in vitro proliferation, migration, apoptosis; tumor size in mouse model [30]; cell adhesion [99]; N-linked glycans: in vitro proliferation, migration, invasion [101]. | Fucosylation Self-assembly of spheroids [102]; EGFR signaling; cell survival in androgen-depleted conditions [31]; vesicles secreted by PCa cells [32]; PSA expression [34]; metastasis to bone [103]. | Biosynthesis of1,6 GlcNAc-Branched N-glycans In vitro invasion; tumor growth in xenograft models [104]. | Mannose Trimming of N-glycans Essential for cell viability [105]. |
Regulation of N-glycosylation Substrate Specificity In vitro proliferation, migration and invasion; xenograft growth in a PTEN negative background; ER structure and stress response; Akt signaling [106]. | O-Linked N-Acetylgalactosamine Addition Essential for cell viability [105]. | O-Linked N-Acetylglucosamine Addition Essential process in androgen-independency [33]; metabolism [107]. | Generation of the Common Core 1 O-glycan Structure Castration resistance and metastasis [108,109]. |
Core-2-branched O-linked glycosylation Tumor growth in mouse model [110,111]; cell adhesion [110]; resistance to NK cell immunity [112]; LNCaP susceptibility to apoptosis induced by Galectin-1 [113]. | Core-3 O-linked glycan formation Tumor formation andmetastasis of PC-3 and LNCaP cells through downregulation of α2β1 integrin complex [114]. | I-branching Migration and invasion; integrin signaling via indirect mechanisms; in DU145 cells appears to largely occur on glycolipids and partially on O-glycans [115]. | Legend: N-acetylglucosamine N-acetylgalactosamine Galactose Mannose Sialic acid Fucose |
(Component of) E3 Ligase | Description | Affected Protein(s) and/or Signaling Pathways | Effects on Processes |
---|---|---|---|
RING type | |||
AMFR | RING-type E3 ubiquitin transferase, component of a complex that participates in the final step of ER-associated degradation | 3βHSD1 [140] | DHT synthesis necessary to activate the AR [140] |
APC/C | Multi-subunit cullin-RING E3 ubiquitin ligase that regulates progression through the metaphase to anaphase of the cell cycle | Cyclin A2, Geminin, PLK1, Aurora A, and CDC20 [141]; SKP2 [142] | PTEN loss but not phosphatase inactivation results in hypersensitivity to pharmacological inhibition of APC-CDH1 targets PLK1 and Aurora A [141]; cell cycle [142] |
BIRC6 | Consists of a BIR and a ubiquitin-conjugating (UBC) domain with chimeric E2/E3 ubiquitin ligase activity; through its BIR domain binds to active caspases; through its UBC domain, facilitates proteasomal degradation of pro-apoptotic proteins | GPCR and matrisome signaling; prosurvival genes [143] | Implicated in advanced, Enzalutamide (Enz)-resistant PCa [143]; role in PCa progression and treatment resistance [144] |
BMI1 | Contains a RING motif; it does not have E3 ubiquitin ligase activities; forms a complex with RING1B to ubiquitinate H2A-K119 and repress the expression levels of polycomb repressive complex 1 (PRC1) targets | AR [135] | PRC1-independent role in MDM2-mediated AR protein degradation; tumor growth of xenografts that have developed resistance to surgical castration and Enz treatment [135] |
CAND1 | F-box protein exchange factor; key assembly factor of SCF E3 ubiquitin ligase complexes | p21 [145]; PLK4 [146] | In vitro cell viability, proliferation, apoptosis [145]; centriole overduplication [146] |
c-CBL | RING domain E3 ligase | EGFR [147] | EGFR/Erk1/2 signaling-mediated PCa [147] |
COP1 | RING-type E3 ubiquitin transferase | STAT3 [148]; ETS transcription factors [149] | Tumorigenesis; proliferation and cancer stem-like properties in prostate epithelial cells [148,149] |
CRL4/Cdt2 | Proliferating cell nuclear antigen (PCNA)-dependent E3 ubiquitin ligase | WHSC1 [150] | Interaction with key intracellular signaling molecules, AKT, RICTOR, and Rac1, to drive PCa metastasis [150] |
CUL3 | Cullin–RING-based E3 ubiquitin ligase | Mutated in a subset of PCa indicating possible driving roles [151] | |
CUL4A | Cullin family of ubiquitin ligase proteins | AR [152] | AR protein homeostasis [152] |
CUL4B | Scaffold protein that assembles the Cullin4B-RING E3 ligase complex | BMI1 [153], c-MYC [154] | Cancer stem-like traits of PCa cells [153]; PCa progression [154] |
FBXL2 | F-box protein; the receptor subunit of one of 69 human SCF ubiquitin ligase complexes | IP3R3 [155] | Ca2+-mediated apoptosis and tumor growth [155] |
FBXL4 | Member of the F-box protein family; part of a modular E3 SCF ubiquitin ligase complexes | Potentially ERLEC1 [156] | PCa progression and metastasis [156] |
FBXL7 | F-box protein that functions as substrate receptor for SCF | c-SRC [157] | Epithelial-to-mesenchymal transition (EMT) and metastasis [157] |
FBXO45 | Substrate-specific adaptor subunit of SCF E3 ubiquitin ligase complex | PAR4 [158,159] | Cell survival [158,159]; therapy resistance [159] |
FBXW7 | F-box and WD repeat domain containing 7 | AURKA [160] | Pathogenesis of prostatic small cell neuroendocrine carcinoma [160] |
FBW7 | F-box protein; a substrate receptor for SCF-type E3 ligase | Dual phosphorylated ERG [161] | Driving of prostate oncogenesis [161] |
KLHL20 | Substrate-binding subunit of Cullin3 ligase | PML, HIF-1α [162] | PCa progression [162] |
MARCH5 | RING-finger E3 ligase | MCL1 [163] | Apoptosis in response to a BH3 mimetic agent targeting BCLXL [163] |
MDM2 | The RING domain E3 ubiquitin ligase; key regulator of p53 tumor suppressor protein activity and stability | AR [164,165]; p53 [166,167]; E2F1 [168]; AR-v7 [169]; E-cadherin [170]; activation of p53 and destabilization of AR by combinatorial inhibition of MDM2 and MDMX [171] | Phosphorylation-dependent ubiquitination and degradation of AR by AKT [165]; stem cell integrity [164]; survival and proliferation of genomically unstable tumor cells [167]; prolongs the half-life of the E2F1 protein by inhibiting its ubiquitination (MDM2 displaces SCFSKP2); influences cell proliferation [168] |
MYCBP2 | Atypical E3 ubiquitin-protein ligase, which mediates ubiquitination of threonine and serine, instead of lysine residues | AR, MYC [138] | Tumorigenicity of AR-positive PCa cells [138] |
MYLIP | E3 ubiquitin-protein ligase whose activity depends on E2 enzymes of the UBE2D family | AR [172] | AR activity [172] |
PIRH2 | Ring finger protein with ubiquitin ligase activity | Epsilon-COP [173]; HDAC1 [174] | Regulation of the secretion of PSA [173]; AR signaling [174] |
pVHL | Substrate recognition subunit of the VHL-Elongin B/C E3 ligase complex that targets the HIF-1/2 for proteasomal degradation under normoxia conditions | AR (enhanced AR de-ubiquitination instead of inducing AR ubiquitination) [175]; HIF-1α [176] | Suppression of AR activity [175]; HIF-1 hypoxic response [176] |
RNF2 | Also known as RING1b or RING2; catalytic subunit of PRC1 | TXNIP [177]; CCL2 [178] | Cell cycle arrest and apoptosis [177]; metastasis in mice inoculated intracardially with PC-3M cells [178] |
RNF6 | RING finger-type E3 ligase | Poly- and mono-ubiquitination of AR [179] | Promotes AR transcriptional activity and specificity [179] |
RNF7 | RING component of CRL (Cullin-RING ligase) | PHLPP1 and DEPTOR (PI3K/AKT/mTOR axis) [180]; p21, p27, NOXA; ERK1/2 signaling [181] | Proliferation in monolayer and soft agar; clonogenic survival; migration [180]; PCa tumorigenesis [181] |
RNF11 | RING finger-type E3 ligase | ErbB2 and EGFR [182] | Growth arrest [182] |
RNF20 and RNF40 | Histone H2B ubiquitin E3 ligases | AR, several cell cycle promoters [183] | Proliferation (due to changed expression of several cell cycle promoters) and modulation of AR transcriptional activity in intact cells [183] |
RNF41 | Ring Finger Protein 41, E3 ligase | ErbB3 [184] | AR-independent proliferation [184] |
RNF126 | E3 ligase that contributes to BAG6-mediated quality control | p21 [185] | Proliferation [185] |
SIAH2 | E3 RING finger ubiquitin ligase; member of the seven in absentia homolog (SIAH) family | EAF2 [186]; AR [137]; AR-V7 [187]; HIF-1α and FOXA2 [136]; Wnt/β-catenin signaling [188] | Apoptosis [186]; lipid metabolism, cell motility, proliferation, cell growth under androgen-deprivation condition in vitro and in vivo, PCa regression upon castration [137]; castration-resistance in PCa therapy [187]; formation of neuroendocrine phenotype and neuroendocrine prostate tumors [136]; inducing and maintaining PCa cells dormancy in bone [188]; death receptor-mediated apoptosis [189] |
SKP2 | F-box protein; crucial component of the SCF (Skp1-Cullin1-F-box) type of E3 ubiquitin ligase complexes | EZH2 [190]; p27 [191,192,193]; JARID1B [194]; DAB2IP [195]; AKT [196]; BRCA2 [197]; ATF4, p27, p21 [198]; Twist [199]; AR [139]; IDH1/2 [200]; FOXO3 [201]; E-cadherin [202] | TRAF6-mediated ubiquitination of EZH2; progression of PCa and CRPC through upregulation and activation of progenitor genes, as well as AR-target genes [190]; paclitaxel resistance [191]; tumorigenesis [192,193,194,195,196]; proliferation, survival, glucose uptake [196]; homologous recombination and sensitivity to the PARP inhibitor rucaparib [197]; oncogenic-stress-driven senescence [198]; progression and stem cell features of CRPC [199]; cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle [200]; cell migration [202]; high expression is associated with a mesenchymal phenotype and increased tumorigenic potential [203] |
SOCS2 | Probable substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin ligase complex | FLT3 and JAK2 [204]; NDR1 stability; NF-κB transactivation [205] | Metastasis formation [204]; SOCS2-deficiency leads to hyper-activation of NF-κB and downstream pathological implications [205] |
TOPORS | RING domain containing E3 ligase | NKX3.1 [206] | Tumor progression [206] |
TRAF4 | RING domain E3 ubiquitin ligase | TrkA [207] | Metastasis formation [207] |
TRAF6 | RING domain E3 ubiquitin ligase | p85a [208]; TGFβ type I receptor [209,210]; PS1 [210]; mTOR [211]; AKT [196]; TAK1 [212]; EZH2 [190] | PI3K/AKT signaling; migration [208]; tumor-promoting effects of TGFβ type I receptor [209,210]; activation of mTOR; regulation of autophagy and cell proliferation [211]; proliferation, survival, glucose uptake, in vivo tumor growth [196]; activation of NF-κB signaling downstream of several receptors [212] |
TRIM11 | E3 ubiquitin-protein ligase; the TRIM motif contains a RING domain | Cell proliferation in vitro and the progression of PCa [213] | |
TRIM16 | It lacks a RING domain found in other TRIM proteins, but can dimerize with other TRIM proteins and has E3 ubiquitin ligase activity | SNAIL signaling pathway [214] | Progression of prostate tumors [214] |
TRIM25 | RING domain E3 ubiquitin ligase | ERG [215]; G3BP2 [216] | Driving of prostate carcinogenesis [215]; cell growth and survival by modulating p53 signals [216] |
β-TrCP | Substrate recognition subunit for the SCFβ-TrCP E3 ligases | HIF-1α [217], Twist [199]; CHD1 [218]; MTSS1 [219]; REST [220]; δ-catenin [221]; AhR [222]; Gli2 [223] | Progression and stem cell features of CRPC [199]; transcription of the pro-tumorigenic TNF–NF-κB gene network [218]; proliferation and migration [219]; AR activity [220]; cell growth [222] |
UHRF1 | Ubiquitin Like with PHD And Ring Finger Domains 1; E3 ubiquitin ligase | Cell proliferation and biochemical recurrence after radical prostatectomy [224]; epigenetic crosstalk and PCa progression [225] | |
RBR type | |||
PRKN | Parkin RBR E3 Ubiquitin Protein Ligase | Participates in removal of damaged mitochondria via mitophagy [226] | |
U-box type | |||
CHIP | U-box type chaperone associated E3 ligase | JMJD1A [227]; SNPH [228]; AR/AR-V7 [229]; AKT signaling pathway [230]; AR [231,232,233]; HIF-1α [234]; PRMT5 [235]; PTEN [236] | AR activity [227]; mitochondrial dynamics, tumor chemotaxis, invasion, and metastasis in vivo [228]; anti-androgen resistance [229]; in vitro migration and invasion [230]; mitotic arrest [233]; potential role in PCa oncogenesis through PRMT5 [235] |
UBE4A | Ubiquitin-protein ligase that probably functions as an E3 ligase; may also function as an E4 ligase complementing actions of another E3 ubiquitin ligase | Interleukin-like EMT inducer (ILEI) [237] | In vitro migration and invasion [237] |
HECT type | |||
EDD | E3 ubiquitin-protein ligase, which is a component of the N-end rule pathway | Wnt/β-Catenin signaling [238] | Sensitivity of hormone-refractory PCa to docetaxel in vitro and in vivo [238] |
E6AP | The founding member of the HECT (Homologous to E6AP Carboxyl Terminus) domain E3 ligases | NDRG1 [239], p27 [240]; PI3K, AKT [241,242], mTOR [241] | Acquisition of mesenchymal features, migration, ability for anchorage-independent growth [239]; tumor growth [240]; proliferation and invasion in bone metastasis [241]; cell growth, proliferation, apoptosis [242]; cellular senescence in vivo, radiation-induced cell death [243] |
HACE1 | HECT domain and ankyrin repeat-containing ubiquitin ligase | HACE1 is a critical chromosome 6q21 tumor suppressor involved in prostate cancer [244] | |
HECTD4 | Probable HECT domain E3 ubiquitin-protein ligase | AR, MYC [138] | Tumorigenicity of AR-positive PCa cells [138] |
HUWE1 | WWE domain-containing protein 1, E3 ubiquitin protein ligase | HK2 [245]; c-MYC [246,247] | Metabolism and cancer stem cell expansion [245]; survival [246]; proliferation [246,247] and migration in vitro, and explant growth in vivo [247] |
ITCH/AIP4 | HECT-type E3 ubiquitin transferase Itchy homolog | ErbB3 [248] | ErbB3 ubiquitination and degradation in cancer cells through JNK1/2-dependent ITCH/AIP4 activation [248] |
Nedd4 | Comprised of a catalytic C-terminal HECT domain and N-terminal C2 domain and WW domains responsible for cellular localization and substrate recognition | IRS-2 [249]; AR [250]; ErbB3 levels and signaling [251] | IGF signaling and mitogenic activity [249]; cancer cell proliferation in vitro and in vivo; sensitization of cancer cells for growth inhibition by an anti-ErbB3 antibody [251] |
SMURF1 | SMAD specific E3 ubiquitin protein ligase 1 | PTEN [252] | PCa progression [252]; invasion [253] |
WWP1 | WW domain-containing E3 ubiquitin protein ligase-1 | TGFβ [254]; p63 [255]; KLF5 [256] | Migration and invasion [257]; 22Rv1 cells colony formation; PC-3 cells proliferation and TGFβ-mediated growth inhibition [254]; apoptosis [255] |
WWP2 | WW Domain Containing E3 Ubiquitin Protein Ligase 2 | SUMO1-modified PTEN [258] | PCa development [258] |
Enzyme | Involvement(s) in Prostate Cancer | Ref. |
---|---|---|
KATs | ||
KAT2A | KAT2A inhibition prevents interleukin (IL) 6-induced PCa metastases through PI3K/PTEN/AKT signaling by inactivating Egr-1 | [307] |
Association between AR and histone acetyltransferase KAT2A increases histone H3 acetylation level on cis-regulatory elements of AR target genes | [308] | |
KAT2B | Promotes PKM2 acetylation and decreases PKM2 protein level through degradation through chaperone-mediated autophagy; promotes tumor growth | [309] |
CBP (KAT3A) | CBP loss cooperates with PTEN haploinsufficiency to drive PCa | [310] |
p300 (KAT3B) | p300-mediated acetylation of histone demethylase JMJD1A prevents its degradation by CHIP and enhances its activity | [227] |
p300/CBP inhibition enhances the efficacy of programmed death-ligand 1 blockade treatment | [311] | |
Therapeutic targeting of the CBP/p300 bromodomain blocks the growth of CRPC | [312] | |
p300 regulates fatty acid synthase expression, lipid metabolism and PCa growth | [313] | |
p300 regulates AR degradation and PTEN-deficient prostate tumorigenesis | [314] | |
The assembly of a macromolecular complex involving CBP/p300 results in acetylation of p53 at K373, a critical PTM required for its biological activity | [315] | |
SKP2 is acetylated by p300 at K68 and K71, which promotes its cytoplasmic retention, and cytoplasmic SKP2 enhances cellular migration through ubiquitination and destruction of E-cadherin | [202] | |
p300 is the dominant coregulator of the CBP/p300 pair for androgen-regulated gene expression in C4-2B cells; p300 is required at an early stage of chromatin remodeling and transcription complex assembly after binding of AR to the gene but before many critical histone modifications occur | [316] | |
Function in the survival and invasion pathways of PCa cell lines | [317] | |
p300 and CBP stimulate estrogen receptor-beta (ER-β) signaling and regulate cellular events in PCa | [318] | |
IL-4 activates AR through enhanced expression of CBP/p300 and its histone acetyltransferase activity | [319] | |
p300 modulates nuclear morphology in PCa and is required for androgen depletion independent activation of the AR | [320] | |
p300 mediates STAT3 acetylation on Lys685, which mediates STAT3 dimerization and is reversible by type I HDAC | [321] | |
CBP/p300 is a component of a transcriptional complex that regulates SRC-dependent hypoxia-induced expression of VEGF | [322] | |
The downregulation of p300 inhibits PCa cell proliferation both at the basal level and on IL6 stimulation | [323] | |
p300 mediates androgen-independent transactivation of the AR by IL6 | [324] | |
p300 and p300/CBP acetylate the AR at sites governing hormone-dependent transactivation | [325] | |
Tip60 (KAT5) | Negatively regulates the proliferation of LNCaP cells via the caspase 3-dependent apoptosis pathway | [326] |
Associated with resistance to X-ray irradiation | [327] | |
Inhibition by TH1834 increases the effect of ionizing radiation in PC-3 and DU145 cells, induces apoptosis and increases unrepaired DNA damage | [328] | |
Interacts with ER-β to regulate endogenous gene expression such as CXCL12 and cyclin D2 | [329,330] | |
KAT5 and KAT6B positively regulate cell proliferation through PI3K/AKT signaling | [331] | |
Inhibition by NU9056 induces a decrease of AR, PSA, p21 and p53 levels in LNCaP cells, which might explain the increase of apoptosis and the decrease of proliferation | [332] | |
Overexpression increases the acetylation of the AR and its localization in the nucleus and promotes cell proliferation | [333] | |
Tip60 and β-catenin complexes regulate expression of metastasis suppressor gene KAI1 | [334] | |
A possible role for Tip60 in the molecular pathway leading to the development of androgen-independent PCa following long-term androgen deprivation therapy | [335] | |
Tip60 and HDAC1 regulate AR activity through changes to the acetylation status of the receptor | [336] | |
MYST1 (KAT8) | Regulates androgen signaling in PCa cells | [337] |
Regulates NF-κB and AR functions during proliferation of PCa cells | [338] | |
FOXP3 induces H4K16 acetylation and H3K4 trimethylation and activation of multiple genes by recruiting KAT8 and causing displacement of PLU-1 | [339] | |
KDACs | ||
Class I | Maspin induction is a critical epigenetic event altered by class I HDACs in the restoration of balance to delay proliferation and migration ability of PCa cells | [340] |
HDAC1 | KLF5 inhibits STAT3 activity and tumor metastasis in PCa by suppressing IGF1 transcription cooperatively with HDAC1 | [341] |
Involved in E-cadherin expression in PCa cells | [342] | |
Ubiquitination of the AR and HDAC1 may constitute an additional mechanism for regulating AR function; HDAC1 and MDM2 function co-operatively to reduce AR mediated transcription that is attenuated by the HAT activity of the AR co-activator Tip60 | [343] | |
HDAC3 | Genetic knockdown of either HDAC1 or HDAC3 can suppress expression of AR-regulated genes, recapitulating the effect of HDAC inhibitor treatment | [344] |
HDAC4 | Positive regulator of AR SUMOylation, revealing a deacetylase-independent mechanism of HDAC action in PCa cells | [345] |
Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative PCa | [346] | |
HDAC6 | Synergistic interaction with MEK-inhibitors in CRPC cells | [347] |
Metastatic prostate cancer-associated p62 inhibits autophagy flux and promotes EMT by sustaining the level of HDAC6 | [348] | |
Regulates AR hypersensitivity and nuclear localization via modulating Hsp90 acetylation in CRPC | [349] | |
HDAC7 | HDAC7 localizes to the mitochondrial inner membrane space of prostate epithelial cells and exhibits cytoplasmic relocalization in response to initiation of the apoptotic cascade, which highlights a link between HDACs, mitochondria, and programmed cell death | [350] |
HDAC11 | HDAC11 depletion is sufficient to cause cell death and to inhibit metabolic activity in PC-3 cells | [351] |
SIRT1 | Modulates the sensitivity of PCa cells to vesicular stomatitis virus oncolysis | [352] |
Mesenchymal stem cells overexpressing SIRT1 inhibit PCa growth by recruiting NK cells and macrophages | [353] | |
Loss of miR-449a in ERG-associated PCa promotes the invasive phenotype by inducing SIRT1 | [354] | |
SIRT1 and LSD1 competitively regulate KU70 functions in DNA repair and mutation acquisition | [355] | |
The silencing of SIRT1 gene in PC-3 cells suppresses the movement, migration, and invasion, possibly via reversing the EMT process | [356] | |
Loss of Sirt1 promotes prostatic intraepithelial neoplasia, reduces mitophagy, and delays Park2 translocation to mitochondria | [226] | |
Existence of SIRT1 and MPP8 crosstalk in E-cadherin gene silencing and EMT | [357] | |
Regulation of histone H2A.Z expression is mediated by SIRT1 in PCa | [358] | |
Enhances matrix metalloproteinase-2 expression and tumor cell invasion of PCa cells | [359] | |
SIRT1 induces EMT by cooperating with EMT transcription factors and enhances PCa cell migration and metastasis | [360] | |
Inhibition of cortactin and SIRT1 expression attenuates migration and invasion of DU145 cells | [361] | |
Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to SKP2-mediated FOXO3 ubiquitination and degradation | [201] | |
Disruption of a SIRT1-dependent autophagy checkpoint in the prostate results in prostatic intraepithelial neoplasia lesion formation | [362] | |
Inhibition of SIRT1 activity increases the chemosensitivity of androgen-refractory PCa cells | [363] | |
SIRT1 inhibition at the activity level as well as via shRNA results in a significant inhibition in the growth and viability of human PCa cells; inhibition of SIRT1 causes an increase in FOXO1 acetylation and transcriptional activation in PCa cells | [364] | |
SIRT1 inhibition causes a decrease in cell growth, cell viability and the colony formation ability and an increase in FOXO1 acetylation and subsequent transcriptional activation regardless of p53 status; SIRT1 inhibition results in an increase in senescence in PC-3-p53 (wild type p53) cells whereas it results in an increase in apoptosis in PC-3 (lack p53) cells | [365] | |
Upregulation of SIRT1 expression may play an important role in promoting cell growth and chemoresistance in androgen-refractory PC-3 and DU145 cells | [366] | |
Required for antagonist-induced transcriptional repression of androgen-responsive genes by the AR | [367] | |
SIRT1 is a regulator of AR expression and function | [368] | |
FOXO1 activity in PCa cells is inhibited by deacetylation by SIRT1 | [369] | |
SIRT2 | Dysregulation of SIRT2 and histone H3K18 acetylation pathways associates with adverse PCa outcomes | [370] |
SIRT3 | Transcriptional repression of SIRT3 potentiates mitochondrial aconitase activation to drive aggressive PCa to the bone | [371] |
SIRT3 and SIRT6 promote PCa progression by inhibiting necroptosis-mediated innate immune response | [372] | |
Inhibits PCa metastasis through regulation of FOXO3A by suppressing Wnt/β-catenin pathway | [373] | |
Inhibits PCa by destabilizing c-MYC through regulation of the PI3K/AKT pathway | [374] | |
Inactivation of SIRT3 leads to elevated SKP2 acetylation, which leads to increased SKP2 stability through impairment of the CDH1-mediated proteolysis pathway resulting in increase of SKP2 oncogenic function; cells expressing an acetylation-mimetic mutant display enhanced cellular proliferation and tumorigenesis in vivo | [202] | |
SIRT4 | Mitochondrial PAK6 inhibits PCa cell apoptosis via the PAK6-SIRT4-ANT2 complex | [375] |
SIRT5 | SIRT 5 regulates the proliferation, invasion, and migration of PCa cells through acetyl-CoA acetyltransferase 1 | [376] |
SIRT6 | E2F1 enhances glycolysis through suppressing Sirt6 transcription in cancer cells | [377] |
Inhibition of SIRT6 reduces cell viability and increases sensitivity to chemotherapeutics | [378] | |
SIRT7 | SIRT7 depletion inhibits cell proliferation and androgen-induced autophagy by suppressing the AR signaling in PCa | [379] |
Promotes PCa cell aggressiveness and chemoresistance | [380] | |
SIRT7 inactivation reverses metastatic phenotypes | [381] |
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Samaržija, I. Post-Translational Modifications That Drive Prostate Cancer Progression. Biomolecules 2021, 11, 247. https://doi.org/10.3390/biom11020247
Samaržija I. Post-Translational Modifications That Drive Prostate Cancer Progression. Biomolecules. 2021; 11(2):247. https://doi.org/10.3390/biom11020247
Chicago/Turabian StyleSamaržija, Ivana. 2021. "Post-Translational Modifications That Drive Prostate Cancer Progression" Biomolecules 11, no. 2: 247. https://doi.org/10.3390/biom11020247