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Molecular Mediator of Prostate Cancer Progression and Its Implication in Therapy
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Samikshan Dutta, Navatha Shree Sharma, Ridwan Islam, Kaustubh Datta
Mutations in spop (Speckle-type POZ protein) gene (6-15% of PCa) represents a subclass of fusion-negative PCa patients with poor prognosis [219–221]. SPOP is a POZ domain adaptor protein that modulates the transcriptional repression activities of genes and thus involve an error-prone method to repair broken DNA strands. SPOP forms a complex with CULLIN3 E3 ubiquitin ligase, and ubiquitinates for degradation of SRC-3/ AIB1, a cofactor of AR [222]. SPOP mutation therefore can activate AR in castration-resistant prostate cancer [223, 224]. SPOP mutation also activates Hedgehog pathway, polycomb group protein BMI1, which then promotes the progression of prostate cancer [225–227]. SPOP mutations are strongly associated with copy loss of CHD, FOXO3 and PRDM1 and rarely have accompanying mutations in PTEN or PIK3CA or TP53 in localized cancers [228]. SPINK1 overexpression is another molecular event found in 5-10% of PCa, which usually does not show gene rearrangement [229]. Although SPINK expression and ERG-negative status are not always mutually exclusive [230–232], SPINK1 encodes a secreted serine peptidase inhibitor, which may involve EGFR in its tumorigenic effects, and thus promotes an aggressive subtype of PCa [232]. It is strongly associated with copy loss of PTEN [230]. Other genetic events that are detected in fusion-negative prostate cancer are methylation of miR-26a, high expression of EZH2, and deletion of tumor suppressor MAP3K7/TAK1 [233–235].
Breast Cancer Stem Cells and Their Niche: Lethal Seeds in Lethal Soil
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Danuta Balicki, Brian Leyland-Jones, Max S. Wicha
Epigenetic modulation of gene expression is highly abnormal in cancers, which often show aberrant promoter CpG island hypermethylation and transcriptional silencing of tumor suppressor genes and prodifferentiation factors. The aberrant epigenetic landscape of the cancer cell is also characterized by a massive genomic hypomethylation, an altered histone code for critical genes, and a global loss of monoacetylated and trimethylated histone H4 (94). In embryonic stem cells, these genes are maintained in a state that is ready for transcription mediated by a bivalent promoter chromatin pattern consisting of the repressor, histone H3 methylated at Lys27 (H3K27) by polycomb group proteins, plus the activator, methylated H3K4. However, in contrast to embryonic stem cells, embryonic carcinoma cells add two key repressors, dimethylated H3K9 and trimethylated H3K9, which are both associated with DNA hypermethylation in adult cancers (14). Polycomb group proteins reversibly repress genes required for differentiation in embryonic stem cells. Stem cell polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than nontargets, supporting a stem cell origin of cancer where reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal, thereby predisposing to subsequent malignant transformation (95). Thus, cell chromatin patterns and transient silencing of these important regulatory genes in stem or progenitor cells may leave these genes vulnerable to aberrant DNA hypermethylation and heritable gene silencing during tumor initiation and progression.
Introduction to Genomics
Published in Altuna Akalin, Computational Genomics with R, 2020
Silencers are similar to enhancers; however their effect is opposite of enhancers on the transcription of the target gene, and results in decreasing their level of transcription. They contain binding sites for repressive transcription factors. Repressor transcription factors can either block the binding of an activator , directly compete for the same binding site, or induce a repressive chromatin state in which no activator binding is possible. Silencer effects, similar to those of enhancers, are independent of orientation and distance to target genes. In contradiction to this general view, in Drosophila there are two types of silencers, long-range and short-range. Short-range silencers are close to promoters and long-range silencers can silence multiple promoters or enhancers over kilobases away. Like enhancers, silencers bound by repressors may also induce changes in DNA structure by looping and creating higher-order structures. One class of such repressor proteins, which is thought to initiate higher-order structures by looping, is Polycomb group proteins (PcGs).
Role of bromodomain and extraterminal (BET) proteins in prostate cancer
Published in Expert Opinion on Investigational Drugs, 2023
Adel Mandl, Mark C. Markowski, Michael A. Carducci, Emmanuel S. Antonarakis
The lack of biomarkers predicting sensitivity to BET inhibitors limits their application in clinical practice. Thus, there is a need to identify PC subtypes that show the highest degree of growth inhibition and adequately stratify tumors into responders versus non-responders. Further research is needed to determine if the overexpression of individual BET family members influences sensitivity to BET inhibitors. Identifying PC types strongly dependent upon BET proteins for survival might be one way to identify those most sensitive to the inhibitors. Further understanding of BET protein-driven transcriptional regulation mechanisms will likely reveal vulnerabilities that could be exploited using BET inhibitors. Substantial evidence shows that BET inhibitors lead to c-MYC downregulation, suggesting that elevated levels of c-MYC could enhance sensitivity to BET inhibitors and serve as a predictive biomarker. Conversely, SPOP-mutant prostate cancer may be primarily resistant to BET inhibition, as might prostate cancers with constitutive activation of the PI3K-mTOR pathway. Furthermore, there is substantial evidence that changes to the epigenetic landscape mediated by Polycomb group proteins might influence responses to BET inhibitors [112,123]. Future work could provide insights into the potential use of the expression profiles of Polycomb group proteins as putative biomarkers.
Beyond EZH2: is the polycomb protein CBX2 an emerging target for anti-cancer therapy?
Published in Expert Opinion on Therapeutic Targets, 2019
Maïka Jangal, Benjamin Lebeau, Michael Witcher
Indeed, H3K27me3 levels are aberrantly increased in several cancer types due to an overexpression of its writer, the methyl transferase EZH2, or the downregulation of its erasers, the demethylases KDM6A (UTX) and KDM6B (JMJD3) (to be discussed in detail below). For example, EZH2 overexpression is associated with aggressive breast cancer [15], and advanced prostate cancer [16]. The activating EZH2 mutation Y641/Y646, observed in lymphomas, leads to elevated H3K27me3 levels [17]. Similar to its role in stem cell populations where Polycomb Group proteins (PcG) prevent differentiation through repression of lineage specifying factors, elevated H3K27me3 may also dedifferentiate tumor cells to acquire more stem cell like properties [18]. Consistent with this concept, EZH2 was found overexpressed in CD24-/CD44+ breast cancer stem cells originating from primary breast cancer samples or xenograft tumors and was implicated in the expansion of these breast cancer stem cell populations [19]. Due to these data, and other reports that EZH2 acts as an oncogene, H3K27me3 modifying enzymes and recognition complexes were pointed out as potential anti-cancer targets and several chemical molecules inhibiting EZH2 are currently under clinical evaluation.
Differential gene expression of tumor-infiltrating CD4+ T cells in advanced versus early stage colorectal cancer and identification of a gene signature of poor prognosis
Published in OncoImmunology, 2020
Varun Sasidharan Nair, Reem Saleh, Rowaida Z Taha, Salman M Toor, Khaled Murshed, Ayman A Ahmed, Mohamed A Kurer, Mohamed Abu Nada, Fares Al Ejeh, Eyad Elkord
Increasing evidence suggests that epigenetics play an indispensable role in the progression of CRC.16,42,43 It has been reported that epigenetics contribute to cancer progression in three ways: (i) restricting the expression of proliferation-related genes, (ii) chromosomal degradation, and (iii) chromatin dysfunction.44 Moreover, changes in global DNA methylation patterns of TILs influence CRC progression from onset to metastasis.45 Herein, we found that T cell proliferation and differentiation- and cell cycle-related genes were significantly downregulated and chromatin-mediated epigenetic silencing pathways were upregulated in advanced stages of CRC, compared with early stages. These data suggest that chromatin-silencing plays an indispensable role in the progression of CRC. Reports showed that global changes in histone 3 (H3) could be exploited as a promising biomarker in tumor transformation.46,47 Similarly, histone modifiers including polycomb-group proteins (PcGs) are engaged in silencing of key regulatory enzymes during the onset and differentiation of tumor cells,48,49 and play an indispensable role in chromatin remodeling and nuclear reprogramming.50 Additionally, the average number of H3K27me3-enriched genes was reported to be higher in prostate cancer tissues and positively correlates with disease progression.51 Similar to these cancer cell studies, we found that H3K27me3-mediated pathways were significantly upregulated in CD4+ TILs in the advanced stages of CRC. These data rationalize that H3K27me3 could be a key player behind the upregulation of chromatin-silencing pathways in advanced stages of CRC.