Polycomb Directed Cell Fate Decisions in Development and Cancer
Abstract
:1. Introduction
2. PcG Complexes
2.1. Action Modes of PRC2 Molecules
2.2. PRC2 Recruitment
3. PcG Protein Functions and Cell Fate Determination
3.1. Self-Renewal
3.2. Differentiation
3.3. Cell Fate Determination
4. Immune Regulation by EZH2 in TME
4.1. Role of EZH2 in T-Cell Differentiation and Cancer
4.2. Role of EZH2 Function in NK Cells Differentiation and Cancer
4.3. Role of EZH2 Reprogramming Tumor Immunosuppressive Cells
5. Role of EZH2 in Tumoral Metabolism
6. PRC2 Therapeutical Options in Cancer
Clinical Trials Using PCR2 Therapy in Cancer
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Mammals | Drosophila | Arabidopsis | Characteristic Domain | Activity | |
---|---|---|---|---|---|
PRC1 | RING1A/RING1B Bim-1 | dRing/Sce | AtRING1A/AtRING1B | RING finger domain [49] | E3 ubiquitin ligase activity for H2A |
PCGF1-6 | Psc | AtBMI1A/ AtBMI1B/ AtBMI1C | RING finger domain | Co-factors for H2A monoubiquitination | |
CBX2/4/6/7/8 | Pc | EMF1 LHP1(TFL2)VRN1 VAL1/2/3 | Chromodomain | Recognizes and binds to H3K27me3 | |
PHC1/ PHC2/ PCH3 | Ph | UNKNOWN | Sterile Alpha Motif (SAM) domain and Zinc finger domain | Mediates monoubiquitinaiton of histone H2A [50] | |
PRC2 | EZH1/2 | E(z) | CLF/ SWN/ MEA | SET domain | H3K27 methyltransferase [51] |
SUZ12 | Su(z)12 | EMF2/ VRN2/ FIS2 | Zinc finger | Mediates core PRC2 and accessory components’ interaction [51] | |
EED | Esc | FIE | WD-40 repeat domain | Stabilizes and enhances E(z) [52] | |
RBAP48/46 | P55/Nurf55 | MSI1-5 | WD-40 repeat domain | Binds to histones and Su(z)12 | |
EZHIP | tissue-specific cofactor of PRC2 | Limits PRC2-mediated H3K27me3 deposition [53] | |||
PRC2.1 | PCL1/2/3 | Pcl | PHD finger, TUDOR | Promotes PRC2 recruitment to CpG islands that lack H3K27m3 mark | |
EPOP or PALI1/2 | |||||
PRC2.2 | JARID2 | Zinc finger, ARID domain, JmjC and JmjN | Promotes the PRC2 recruitment to chromatin that has PcG-dependent modifications | ||
AEBP2 | Zinc finger |
Subgroup | Compound | Clinical Trial | Phase | Clinical Trial Identifier | Status |
---|---|---|---|---|---|
EZH2 inhibitors | Tazemetostat | Patients with relapsed, refractory follicular lymphoma | III | NCT04224493 | Recruiting |
In combination with pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma | I/II | NCT03854474 | Recruiting | ||
Patients with moderate and severe hepatic impairment with advanced malignancies | I | NCT04241835 | Recruiting | ||
Patients with refractory B-cell non-Hodgkin’s lymphoma with EZH2 gene mutation | II | NCT03456726 | Active | ||
Patients with recurrent ovarian or endometrial cancer | II | NCT03348631 | Suspended | ||
Patients with B-cell lymphoma or advance solid tumors | I | NCT03010982 | Completed | ||
Patients with mCRPC (+abiraterone/prednisone or enzalutamide) | II | NCT02875548 | Ongoing | ||
Patients with advanced epithelioid sarcoma in combination with doxorubicin | III | NCT04204841 | Recruiting | ||
Prelapsed or refractory INI-1 negative tumors or synovial sarcoma, rhabdoid tumors, malignant rhabdoid tumors of ovary | I | NCT02601937 | Recruiting | ||
In combination with Atezolizumab and Obinutuzumab in relapsed/refractory follicular Lymphoma and diffuse Large B-cell Lymphoma | I | NTC02220842 | Completed | ||
In combination with doxorubicin and HCI for advanced soft-tissue sarcoma or epitheloid sarcoma | III | NCT04204941 | Recruiting | ||
CPI-1205 | ProSTAT: Patients with mCRPC in combination with abiraterone/prednisone (ARPI) | II | NCT03480646 | Recruiting | |
ORIO-E: Patients with advanced solid tumors in combination with ipilimumab | I/II | NCT03525795 | Recruiting | ||
Patients with B-cell lymphomas | I | NCT02395601 | Completed | ||
Hepatic impairment advanced malignant solid tumor | I | NCT04241835 | Recruiting | ||
CPI-0209 | Patients with advanced solid tumors in combination with irinotecam | I/II | NCT04104776 | Recruiting | |
Valemetostat | Patients with acute myelogenous leukemia or acute lymphocytic leukaemia | I/II | NCT03110354 | Completed | |
Patients with recurrent SCLC in combination with irinotecam | I/II | NCT03879798 | Recruiting | ||
Patients with non-Hodgkin lymphoma (NHL) | I | NCT02732275 | Active | ||
Patients with relapsed/refractory adult T-cell leukaemia or lymphoma | II | NCT04102150 | Active | ||
Participants with hepatic impairments (single-dose) | I | NCT04276662 | Completed | ||
PF-06821497 | Patients with follicular lymphoma, CRPC and relapsed/refractory small cell lung cancer (SCLC) | I | NCT03460977 | Recruiting | |
SHR2554 | Relapsed or refractory mature lymphoid neoplams | I | NCT03741712 | Recruiting | |
SHR2554 | In combination with SHR3680 (inhibits androgen-mediated translocation of AR) in CRPC | I/II | NCT03460977 | Recruiting | |
EPZ-6438+ARPI | CELLO-1: Patients with mCRPC who have not received chemotherapy | I/II | NCT04179864 | Recruiting | |
Dual EZH2 inhibitors | DS-3201b | Patients with hepatic impairment (single dose DS-3201b) | I | NCT04276662 | Recruiting |
Patients with adult T-cell leukemia/lymphoma | II | NCT04102150 | Recruiting | ||
Patients with SCLC with irinotecam | I/II | NCT3879798 | Recruiting | ||
Patients with lymphomas | I | NCT02732275 | Recruiting | ||
EED inhibitors | MAK683 | Patients with advanced malignancies (diffuse large B cell lymphoma) | I/II | NCT02900561 | Recruiting |
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German, B.; Ellis, L. Polycomb Directed Cell Fate Decisions in Development and Cancer. Epigenomes 2022, 6, 28. https://doi.org/10.3390/epigenomes6030028
German B, Ellis L. Polycomb Directed Cell Fate Decisions in Development and Cancer. Epigenomes. 2022; 6(3):28. https://doi.org/10.3390/epigenomes6030028
Chicago/Turabian StyleGerman, Beatriz, and Leigh Ellis. 2022. "Polycomb Directed Cell Fate Decisions in Development and Cancer" Epigenomes 6, no. 3: 28. https://doi.org/10.3390/epigenomes6030028