Search Results (43)

Background/Objective: Aberrant acetylation and methylation of histone and non-histone proteins contribute to carcinogenesis. Among non-histone proteins, wild-type (wt) p53 is particularly notable for the critical role that acetylation and methylation play in regulating its stability and function. Although with opposite outcomes, these post-translational modifications (PTMs) can also affect mutant forms of p53 (mutp53), which are frequently detected in cancers. These proteins may acquire oncogenic properties, activating signaling pathways that promote carcinogenesis. Acetylation activates wtp53, while this PTM has been shown to destabilize mutp53, reducing cancer aggressiveness and improving the efficacy of anticancer therapies. In this study, we investigated the possibility of targeting mutp53 in pancreatic cancer cells by using a combination of EZH2 and HDAC inhibitors. Methods: Western blotting, qRT-PCR, and ChIP experiments were performed to address this question. Results: We found that the EZH2 inhibitor Valemetostat (DS) in combination with the histone deacetylase inhibitor SAHA displaced the SET/TAF-Iβ oncoprotein from mutp53 and increased its interaction with the acetyltransferase p300, which was responsible for p53 acetylation. Moreover, mutp53 was downregulated, p21 was upregulated, and CHK1 was reduced, increasing DNA damage and leading to a stronger impairment of pancreatic cancer cell survival compared with single-agent treatments. Conclusions: Our results reveal that combining epigenetic drugs such as Valemetostat and SAHA could be exploited to target mutp53 and improve the outcome of treatments for aggressive tumors harboring it, such as in pancreatic cancer. Full article

Curcumin-mediated anti-cancer properties have been correlated with the inhibition of oncogenic molecules such as mutp53 and c-Myc. Their targeting is therapeutically significant, as p53, following point mutations, can acquire oncogenic functions, and c-Myc overexpression, due to translocations, point mutations, protein/protein interactions, or epigenetic modifications, plays a central role in cancer cell proliferation and metabolic reprogramming, particularly in colorectal cancer. In a previous study, we showed that curcumin strongly downregulated mutp53 while activating wtp53 and reduced the expression of methyltransferases such as EZH2, G9a, and MLL-1 in colon cancer cells. Based on this background, here we investigated whether the dysregulation of such methyltransferases could correlate with the effect observed on p53. We also explored whether these epigenetic changes could affect c-Myc expression in these cells. By Western blot analysis and RT-qPCR, we found that the downregulation of EZH2; G9a; and, to a lesser extent, KDM1, which was also reduced by curcumin, correlated with the decrease in mutp53 and that the reduction of EZH2 and KDM1 correlated with the activation of wtp53. Regarding c-Myc, we unveiled the occurrence of a positive feedback loop between it and MLL-1, which was inhibited by curcumin, independently of the p53 status. In conclusion, this study provides new insights into the therapeutic potential of curcumin, which involves its properties to act as an epigenetic modulator and target key molecules in colon cancer cells. Full article

Epigenetic abnormalities play a critical role in colon carcinogenesis, making them a promising target for therapeutic interventions. In this study, we demonstrated that curcumin reduces colon cancer cell survival and that a decrease in lysine methylation was involved in such an effect. This correlated with the downregulation of methyltransferases EZH2, MLL1, and G9a, in both wild-type p53 (wtp53) HCT116 cells and mutant p53 (mutp53) SW480 cells, as well as SET7/9 specifically in wtp53 HCT116 cells. The effects induced by curcumin were more pronounced in wtp53 cells, where it induced a stronger apoptosis and ferroptosis. Interestingly, curcumin also reduced mutp53 expression, suggesting that it could enhance the efficacy of other therapies, particularly in overcoming drug resistance mechanisms associated with mutp53. For instance, in this study, we show that curcumin sensitized SW480 cells to SET7/9 inhibition by sinefungin, further supporting its potential as a combinatorial therapeutic agent. However, although to a lesser extent, curcumin also impaired cell survival in HCT 116 p53 null cells, suggesting that other molecular pathways or factors, beyond p53, may be involved in curcumin-induced cytotoxicity. Full article

The exploration of drug targets has always been a priority in new drug research, and this work is even more essential for natural active compounds. Saxifraga tangutica is a traditional Tibetan medicine with excellent antioxidant properties. In this study, an alkaloid, N-p-coumaroyl-N’-caffeoylputrescine (PCC), was first isolated from the plant, Saxifraga tangutica, with a DPPH scavenging rate of 0.936 μg/mL. To further identify its target, the drug affinity responsive target stability technique and multiple public databases were integrated to retrieve a total of 317 common targets from comprehensive screening. A further bioinformatics analysis not only identified 13 hub targets but also indicated PCC as having biological activities against cancer and affecting metabolic diseases. Integrating reverse virtual docking, molecular dynamics simulations, and cellular thermal shift assays ultimately focused on HSP90AA1 as the target of PCC. An in vitro study on liver (HepG2) cells and breast (MCF-7) cancer cells revealed that PCC modulates HSP90AA1, subsequently affecting Mut-p53 expression, triggering a cascade effect that reduced adriamycin-induced drug resistance in cells. Furthermore, a prediction of the absorption, distribution, metabolism, excretion, and toxicity was also applied to evaluate the drug-like properties of PCC. Overall, the integrated strategy used in this study successfully identified the target of PCC, providing a valuable paradigm for future research on the action targets of natural products. Full article

This review delves into the significant cellular and molecular responses triggered by UVR exposure in human skin, emphasizing the pivotal role of mutant p53 (mutp53) in the carcinogenic process elicited by radiation. By underlining the role of a functional p53 in safeguarding skin cells from UVR-induced damage, this work underscores the potential significance of targeting mutp53, aiming to restore its wild-type-like activity (reactivation), as a protective strategy against skin cancer (SC), particularly NMSC. Most importantly, an interesting crosstalk between p53 and its vitamin D receptor (VDR) transcriptional target is also highlighted in the suppression of skin carcinogenesis, which opens the way to promising chemopreventive strategies involving synergistic combinations between mutp53 reactivators and vitamin D. Collectively, this review not only opens new avenues for future research, but also offers promising prospects for the development of novel beneficial approaches in the field of SC. Full article

Fludioxonil, an antifungal agent used as a pesticide, leaves a measurable residue in fruits and vegetables. It has been identified to cause endocrine disruption, interrupt normal development, and cause various diseases such as cancers. In this study, fludioxonil was examined for its effects on the development and metastasis of breast cancer cells. On fludioxonil exposure (10⁻⁵ M) for 72 h, mutant p53 (mutp53) MDA-MB-231 triple-negative breast cancer (TNBC) cells significantly inhibited cell viability and developed into polyploid giant cancer cells (PGCCs), with an increase in the number of nuclei and expansion in the cell body size. Fludioxonil exposure disrupted the normal cell cycle phase ratio, resulting in a new peak. In addition, PGCCs showed greater motility than the control and were resistant to anticancer drugs, i.e., doxorubicin, cisplatin, and 5-fluorouracil. Cyclin E1, nuclear factor kappa B (NF-κB), and p53 expressions were remarkably increased, and the expression of cell cycle-, epithelial–mesenchymal-transition (EMT)-, and cancer stemness-related proteins were increased in the PGCCs. The daughter cells obtained from PGCCs had the single nucleus but maintained their enlarged cell size and showed greater cell migration ability and resistance to the anticancer agents. Consequently, fludioxonil accumulated Cyclin E1 and promoted the inflammatory cytokine-enriched microenvironment through the up-regulation of TNF and NF-κB which led to the transformation to PGCCs via abnormal cell cycles such as mitotic delay and mitotic slippage in mutp53 TNBC MDA-MB-231 cells. PGCCs and their daughter cells exhibited significant migration ability, chemo-resistance, and cancer stemness. These results strongly suggest that fludioxonil, as an inducer of potential genotoxicity, may induce the formation of PGCCs, leading to the formation of metastatic and stem cell-like breast cancer cells. Full article

Wild-type (wt) p53 and mutant forms (mutp53) play a key but opposite role in carcinogenesis. wtP53 acts as an oncosuppressor, preventing oncogenic transformation, while mutp53, which loses this property, may instead favor this process. This suggests that a better understanding of the mechanisms activating wtp53 while inhibiting mutp53 may help to design more effective anti-cancer treatments. In this review, we examine possible PTMs with which both wt- and mutp53 can be decorated and discuss how their manipulation could represent a possible strategy to control the stability and function of these proteins, focusing in particular on mutp53. The impact of ubiquitination, phosphorylation, acetylation, and methylation of p53, in the context of several solid and hematologic cancers, will be discussed. Finally, we will describe some of the recent studies reporting that wt- and mutp53 may influence the expression and activity of enzymes responsible for epigenetic changes such as acetylation, methylation, and microRNA regulation and the possible consequences of such changes. Full article

Epigenetic changes are common in cancer and include aberrant DNA methylation and histone modifications, including both acetylation or methylation. DNA methylation in the promoter regions and histone deacetylation are usually accompanied by gene silencing, and may lead to the suppression of tumor suppressors in cancer cells. An interaction between epigenetic pathways has been reported that could be exploited to more efficiently target aggressive cancer cells, particularly those against which current treatments usually fail, such as pancreatic cancer. In this study, we explored the possibility to combine the DNA demethylating agent 5-AZA with HDAC inhibitor SAHA to treat pancreatic cancer cell lines, focusing on the acetylation of mutp53 and the consequences on its stability, as well as on the interaction of this protein with c-myc and BRCA-1, key molecules in cancer survival. The results obtained suggest that SAHA/5-AZA combination was more effective than single treatments to promote the degradation of mutp53, to upregulate p21 and downregulate c-Myc and BRCA-1, thus increasing DNA damage and cytotoxicity in pancreatic cancer cells. Full article

The p53 protein is the master regulator of cellular integrity, primarily due to its tumor-suppressing functions. Approximately half of all human cancers carry mutations in the TP53 gene, which not only abrogate the tumor-suppressive functions but also confer p53 mutant proteins with oncogenic potential. The latter is achieved through so-called gain-of-function (GOF) mutations that promote cancer progression, metastasis, and therapy resistance by deregulating transcriptional networks, signaling pathways, metabolism, immune surveillance, and cellular compositions of the microenvironment. Despite recent progress in understanding the complexity of mutp53 in neoplastic development, the exact mechanisms of how mutp53 contributes to cancer development and how they escape proteasomal and lysosomal degradation remain only partially understood. In this review, we address recent findings in the field of oncogenic functions of mutp53 specifically regarding, but not limited to, its implications in metabolic pathways, the secretome of cancer cells, the cancer microenvironment, and the regulating scenarios of the aberrant proteasomal degradation. By analyzing proteasomal and lysosomal protein degradation, as well as its connection with autophagy, we propose new therapeutical approaches that aim to destabilize mutp53 proteins and deactivate its oncogenic functions, thereby providing a fundamental basis for further investigation and rational treatment approaches for TP53-mutated cancers. Full article

Recent studies have shown that thyrocytes are permissive to HHV-6A infection and that the virus may contribute to the pathogenesis of autoimmune thyroiditis. Thyroid autoimmune diseases increase the risk of papillary cancer, which is not surprising considering that chronic inflammation activates pathways that are also pro-oncogenic. Moreover, in this condition, cell proliferation is stimulated as an attempt to repair tissue damage caused by the inflammatory process. Interestingly, it has been reported that the well-differentiated papillary thyroid carcinoma (PTC), the less aggressive form of thyroid tumor, may progress to the more aggressive follicular thyroid carcinoma (FTC) and eventually to the anaplastic thyroid carcinoma (ATC), and that to such progression contributes the presence of an inflammatory/immune suppressive tumor microenvironment. In this study, we investigated whether papillary tumor cells (BCPAP) could be infected by human herpes virus-6A (HHV-6A), and if viral infection could induce effects related to cancer progression. We found that the virus dysregulated the expression of several microRNAs, such as miR-155, miR-9, and the miR-221/222 cluster, which are involved in different steps of carcinogenesis, and increased the secretion of pro-inflammatory cytokines, particularly IL-6, which may also sustain thyroid tumor cell growth and promote cancer progression. Genomic instability and the expression of PTEN, reported to act as an oncogene in mutp53-carrying cells such as BCPAP, also increased following HHV-6A-infection. These findings suggest that a ubiquitous herpesvirus such as HHV-6A, which displays a marked tropism for thyrocytes, could be involved in the progression of PTC towards more aggressive forms of thyroid tumor. Full article

TP53 is the most frequently mutated gene in human cancers. Most TP53 genomic alterations are missense mutations, which cause a loss of its tumour suppressor functions while providing mutant p53 (mut_p53) with oncogenic features (gain-of-function). Loss of p53 tumour suppressor functions alters the transcription of both protein-coding and non-protein-coding genes. Gain-of-function of mut_p53 triggers modification in gene expression as well; however, the impact of mut_p53 on the transcription of the non-protein-coding genes and whether these non-protein-coding genes affect oncogenic properties of cancer cell lines are not fully explored. In this study, we suggested that LINC01605 (also known as lincDUSP) is a long non-coding RNA regulated by mut_p53 and proved that mut_p53 directly regulates LINC01605 by binding to an enhancer region downstream of the LINC01605 locus. We also showed that the loss or downregulation of LINC01605 impairs cell migration in a breast cancer cell line. Eventually, by performing a combined analysis of RNA-seq data generated in mut_TP53-silenced and LINC01605 knockout cells, we showed that LINC01605 and mut_p53 share common gene pathways. Overall, our findings underline the importance of ncRNAs in the mut_p53 network in breast and ovarian cancer cell lines and in particular the importance of LINC01605 in mut_p53 pro-migratory pathways. Full article

p53 plays a critical role in tumor suppression and is the most frequently mutated gene in human cancers. Most p53 mutants (mutp53) are missense mutations and are thus expressed in human cancers. In human cancers that retain wtp53, the wtp53 activities are downregulated through multiple mechanisms. For example, the overexpression of the negative regulators of p53, MDM2/MDMX, can also efficiently destabilize and inactivate wtp53. Therefore, both wtp53 and mutp53 have become promising and intensively explored therapeutic targets for cancer treatment. Current efforts include the development of small molecule compounds to disrupt the interaction between wtp53 and MDM2/MDMX in human cancers expressing wtp53 and to restore wtp53-like activity to p53 mutants in human cancers expressing mutp53. In addition, a synthetic lethality approach has been applied to identify signaling pathways affected by p53 dysfunction, which, when targeted, can lead to cell death. While an intensive search for p53-targeted cancer therapy has produced potential candidates with encouraging preclinical efficacy data, it remains challenging to develop such drugs with good efficacy and safety profiles. A more in-depth understanding of the mechanisms of action of these p53-targeting drugs will help to overcome these challenges. Full article

Background: Whether sex and co-mutations impact prognosis of patients with SMARCA4-mutated (mutSMARCA4) malignancies is not clear. Methods: This cohort included patients from Northern California Kaiser Permanente with next-generation sequencing (NGS) performed from August 2020 to October 2022. We used Cox regression modeling to examine the association between sex and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of treatment, tumor mutation burden (TMB), and TP53, KRAS, CDKN2A, STK11, and Keap1 co-mutations. Results: Out of 9221 cases with NGS performed, 125 cases (1.4%) had a mutSMARCA4. The most common malignancies with a mutSMARCA4 were non-small cell lung cancer (NSCLC, 35.2%), esophageal and stomach adenocarcinoma (12.8%), and cancer of unknown primary (11.2%). The most common co-mutations were p53 (mutp53, 59.2%), KRAS (mutKRAS, 28.8%), CDKN2A (mutCDKN2A, 31.2%), STK11 (mutSTK11, 12.8%), and Keap1 (mutKeap1, 8.8%) mutations. Male patients had substantially worse OS than female patients both among the entire mutSMARCA4 cohort (HR = 1.71, [95% CI 0.92–3.18]) with a median OS of 3.0 versus 43.3 months (p < 0.001), and among the NSCLC subgroup (HR = 14.2, [95% CI 2.76–73.4]) with a median OS of 2.75 months versus un-estimable (p = 0.02). Among all patients with mutSMARCA4, mutp53 versus wtp53 (HR = 2.12, [95% CI 1.04–4.29]) and mutSTK11 versus wtSTK11 (HR = 2.59, [95% CI 0.87–7.73]) were associated with worse OS. Among the NSCLC subgroup, mutp53 versus wtp53 (HR = 0.35, [0.06–1.97]) and mutKRAS versus wtKRAS (HR = 0.04, [0.003-.45]) were associated with better OS, while mutCDKN2A versus wtCDKN2A (HR = 5.04, [1.12–22.32]), mutSTK11 versus wtSTK11 (HR = 13.10, [95% CI 1.16–148.26]), and mutKeap1 versus wtKeap1 (HR = 5.06, [95% CI 0.89–26.61}) were associated with worse OS. Conclusion: In our cohort of patients with mutSMARCA4, males had substantially worse prognosis than females, while mutTP53, mutKRAS, mutCDKN2A, mutSTK11 and mutKeap1were differentially associated with prognosis among all patients and among the NSCLC subgroup. Our results, if confirmed, could suggest potentially unidentified mechanisms that underly this sex and co-mutation-dependent prognostic disparity among patients whose tumor bears a mutSMARCA4. Full article

Mutations in the tumor suppressor p53 (p53) promote cancer progression. This is mainly due to loss of function (LOS) as a tumor suppressor, dominant-negative (DN) activities of missense mutant p53 (mutp53) over wild-type p53 (wtp53), and wtp53-independent oncogenic activities of missense mutp53 by interacting with other tumor suppressors or oncogenes (gain of function: GOF). Since p53 mutations occur in ~50% of human cancers and rarely occur in normal tissues, p53 mutations are cancer-specific and ideal therapeutic targets. Approaches to target p53 mutations include (1) restoration or stabilization of wtp53 conformation from missense mutp53, (2) rescue of p53 nonsense mutations, (3) depletion or degradation of mutp53 proteins, and (4) induction of p53 synthetic lethality or targeting of vulnerabilities imposed by p53 mutations (enhanced YAP/TAZ activities) or deletions (hyperactivated retrotransposons). This review article focuses on clinically available FDA-approved drugs and drugs in clinical trials that target p53 mutations and summarizes their mechanisms of action and activities to suppress cancer progression. Full article

Breast cancer is the most frequent cancer in women. Despite recent clinical advances, new therapeutic approaches are still required. The cystine-glutamate antiporter xCT, encoded by the SLC7A11 gene, which imports cystine in exchange with glutamate, is a potentially new target for breast cancer therapy, being involved in tumor cell redox balance and resistance to therapies. xCT expression is regulated by the oncosuppressor p53, which is mutated in many breast cancers. Indeed, mutant p53 (mut-p53) can induce xCT post-transcriptional down modulation, rendering mut-p53 tumors susceptible to oxidative damage. Interestingly, the drug APR-246, developed to restore the wild-type function of p53 in tumors harboring its mutation, alters the cell redox balance in a p53-independent way, possibly rendering the cells more sensitive to xCT inhibition. Here, we propose a combinatorial treatment based on xCT immunetargeting and APR-246 treatment as a strategy for tackling breast cancer. We demonstrate that combining the inhibition of xCT with the APR-246 drug significantly decreased breast cancer cell viability in vitro and induced apoptosis and affected cancer stem cells’ self-renewal compared to the single treatments. Moreover, the immunetargeting of xCT through DNA vaccination in combination with APR-246 treatment synergistically hinders tumor progression and prevents lung metastasis formation in vivo. These effects can be mediated by the production of anti-xCT antibodies that are able to induce the antibody dependent cellular cytotoxicity of tumor cells. Overall, we demonstrate that DNA vaccination against xCT can synergize with APR-246 treatment and enhance its therapeutic effect. Thus, APR-246 treatment in combination with xCT immunetargeting may open new perspectives in the management of breast cancer. Full article