Commentary
Genetic, epigenetic and environmental factors play disposing role in breast cancer initiation and progression. Oncogenes and tumor suppressor genes act as molecular players acting as activator, repressor or co-activator. Polycomb repressor protein Enhancer of Zeste Homolog 2 (EZH2) predominantly act as repressor protein have shown its substantial contribution in genetic, epigenetic as well as environmental factors induced breast tumor development. It is highly studied repressor protein in all cancer subtypes with more than three hundred publications in the current year. EZH2 is a master regulator of cell fate decisions having role in all potential signaling pathways in one way or the other. By repressing genes responsible for cell differentiation, EZH2 plays imperative role in undifferentiated stage of BRCA1-deficient tumors [1]. At the same time, EZH2 mediated regulation of oncogenes is evident to drive epigenetics, transcriptional and structural alterations in domains of chromatin [2]. Our group revealed critical role of EZH2 in nicotine-mediated increased breast cancer progression [3], thereby signifying its role in environment-induced disease symptoms. Based on indispensable role of EZH2 in breast cancer development, our group identified its contravened targets that significantly associate with overall breast cancer patient survival [4]. Among the identified targets glycoprotein non-metastatic melanoma protein B or GPNMB has recently been reviewed to have potential therapeutic implications in autoimmunity suggesting indirect role of EZH2 in autoimmune disease outcome [5]. Like EZH2, RNA binding protein brefeldin A resistance factor 1(Bfr1) is reported to regulate protein expression of POMT2 that have effects in protein modifications by Protein O-Mannosylation [6]. Using computational studies and KEGG pathway analysis, potential role of another identified target collagen type V α?1chain (COL5A1) has been further investigated in breast cancer [7]. EZH2 is the leading candidate among epigenetic modulators in aggressive triple negative breast cancer [8]. Owing to its carcinogenic role, several research groups identified and developed small molecules that may be used to target EZH2. Recently, an EZH2 selective degrader MS1943 has been generated that show potential cytotoxic effects on triple negative breast cancer cells with high efficacy in vivo conditions [9]. Drug resistance in cancer is complicated and EZH2 inhibition through its specific inhibitors or shRNA/ siRNA sensitizes the established resistance as evidenced by latest reports [10-14]. EZH2 overexpression renews the cancer stem cells and results into increased cancer cell metastasis [15] along with increased resistance towards programmed death 1 (PD1) based therapeutics [16] in cancer. It is closely associated with cancer stem cell properties that favor neoplastic transformation [17]. At the same time, EZH2 knockdown reduced mammosphere formation by repressing the genes that play critical role in promoting cancer stem cell expansion [18].
Functions of vast majority of transcripts from non-protein coding regions of the human genome are now being highly studied. Long non-coding RNAs are the growing focus of cancer genomics providing therapeutic opportunities in cancer growth, metastasis, metabolism and immunity [19,20]. In the current year, role of several long-non-coding RNAs is reported to be EZH2-mediated such as PHACTR2-AS1 [21], LOXL1-AS1 [22], HOTAIRM1 [23], LINC00511 [24], MALAT1 [25], DANCR [26], LINC00021 [27], LncGAS5 [28,29], lncRNA MEG3 [30], ANCR [31], HOTAIR [32-34] and FOXD2-AS1 [35], LINC01419 [36], LncRNA PCAT1 [37,38], lncRNA UFC1 [39], AFAP1-AS1 [40], ANRIL [41], LINC00460 [42], ncRNA UCA1 [11,43-46], NRON [47], SNHG14 [48], SNHG7 [49,50], LINP1 [51], RC3H2 [52], CACNA1G-AS1 [53], ROR1-AS1 [54], HITT [55], NEAT1 [56], Lnc00518 [57], UNC5B-AS1 [58], LATS2-AS1-001 [59], MNX1-AS1 [60] SNHG8 [61], PVT1 [62,63], PSMA3-AS1 [64], Prader Willi/Angelman region RNA5 (PAR5) [65], CDKN2B-AS1 [66], AFAP1-AS1 [67], linc01088 [68], LINC00630 [69], GATA6-AS1 [70], IGF2-AS [71], LNAPPCC [72], BLACAT1 [73], DLX6-AS1 [74], PPP1R1B [75], LEF1-AS1 [76], NR-104098 [77], SNHG7 [78], LINC01234 [79], MRPL23-AS1 [80], ST7-AS1 [81], and OIP5-AS1 [82]. Apart from long-non-coding RNA, role of exosomes is currently among the most studied factors in human malignancies. Surrounded by a lipid bi-layer membrane, exosomes are a subset of extracellular vesicles that are secreted from all types of cells including cancer cells [83]. Exosomes are important players in tumor heterogeneity and chemoresistance [84]. Blood plasma and bioengineered tumor contained high level of EZH2 mRNA. Exosomes were suggested to function as cargo for transfer of EZH2 mRNA into the surrounding mesenchymal stem cells [85]. Recently, role of exosomal miR-25-3p and microRNA-133b from mesenchymal stem cells have been elucidated in myocardial infraction and glioma progression respectively by targeting EZH2, Wnt/ beta-catenin and pro-apoptotic proteins such as FASL and PTEN [86,87]. Exosomal long-non-coding RNAs have also been reported in association with EZH2-mediated epigenetic silencing [28,39]. In association with EZH2, lncRNA MRPL23-AS1 mediates transcriptional silencing of a well-known tumor suppressor and epithelial cell marker, E-cadherin [80]. Another exosomal circRNA_100284 from arsenite-induced transformed cells regulates EZH2 by miR-217 [88]. microRNA profiling of exosomes derived from acute-myeloid leukemia [AML] mesenchymal stem cells, identified relevant miRNAs and gave new insights of leukemogenesis and possible treatment strategies [89]. One of the miRNAs identified in the study was miRNA-101 that regulates the expression of EZH2, which suggested its role in stem cell-like properties of AML. Multifaceted and essential role of EZH2 in cancer had led to identification and development of EZH2 inhibitors. Previously known inhibitors of EZH2 are DZNep, EI1, EPZ005687, GSK343, GSK126, UNC1999, EPZ-6438, SAH-EZH2 and others [90] that are in pre-clinical or phase-I trial. Recent candidates in this list is the second generation inhibitors that show increased efficacy and half-life [91]. Interestingly, in March 2020, FDA has approved the first EZH2 inhibitor namely tazemetostat under the trade name Tazverik™ and epizyme for treatment of adults with locally advanced or metastatic epithelioid sarcoma [92,93] which may also prove promising against hematological malignancies [93]. Through multiple pathways including lipid, glucose and amino acids, EZH2 alters the metabolic profile of tumor cells. Combination of EZH2 inhibitors are now being evaluated as promising anti-tumor therapy in several cancers like B and T-cell lymphoma, bladder and melanoma [94] owing to its vital role in immune system [95]. Yet another new method to identify cancer specific genetic aberrations is to characterize circulating DNA using peripheral blood testing [96]. EZH2 expression in circulating epithelial cells was suggested as promising biomarker for detecting early metastasis in lymphoma and prostate cancer [97,98]. Altogether, an updated research finding further explains the intricate relation between EZH2 & cancer and strengthens its crucial role in disease pathogenesis. Targeting polycomb group protein may formulate new treatment strategies for human malignancies.
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