Goleij Pouya, Heidari Mohammad Mahdi, Tabari Mohammad Amin Khazeei, Hadipour Mahboube, Rezaee Aryan, Javan Alireza, Sanaye Pantea Majma, Larsen Danaé S, Daglia Maria, Khan Haroon
USERN Office, Kermanshah University of Medical Sciences, Kermanshah, 6715847141, Iran.
Immunology Board for Transplantation and Cell-Based Therapeutics (Immunotact), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
Funct Integr Genomics. 2025 Mar 6;25(1):53. doi: 10.1007/s10142-025-01563-8.
Polycomb Repressive Complex 2 (PRC2) is a central regulator of gene expression via the trimethylation of histone H3 on lysine 27. This epigenetic modification plays a crucial role in maintaining cell identity and controlling differentiation, while its dysregulation is closely linked to cancer progression. PRC2 silences tumor suppressor genes, promoting cell proliferation, metastasis, epithelial-mesenchymal transition, and cancer stem cell plasticity. Enhancement of zeste homolog 2 (EZH2) overexpression or gain-of-function mutations have been observed in several cancers, including lymphoma, breast, and prostate cancers, driving aggressive tumor behavior and drug resistance. In addition to EZH2, other PRC2 components, such as embryonic ectoderm development (EED) and suppressor of zeste 12, are essential for complex stability and function. EED, in particular, enhances EZH2 activity and has emerged as a therapeutic target. Inhibitors like MAK683 and EED226 disrupt EED's ability to maintain PRC2 activity, thereby reducing H3K27me3 levels and reactivating tumor suppressor genes. Valemetostat, a dual inhibitor of both EZH2 and EED, has shown promising results in aggressive cancers like diffuse large B-cell lymphoma and small-cell lung cancer, underlining the therapeutic potential of targeting multiple PRC2 components. PRC2's role extends beyond gene repression, as it contributes to metabolic reprogramming in tumors, regulating glycolysis and lipid synthesis to fuel cancer growth. Furthermore, PRC2 is implicated in chemoresistance, particularly by modulating DNA damage response and immune evasion. Tazemetostat, a selective EZH2 inhibitor, has demonstrated significant clinical efficacy in EZH2-mutant cancers, such as non-Hodgkin lymphomas and epithelioid sarcoma. However, the compensatory function of enhancer of zeste homolog 1 (EZH1) in some cancers requires dual inhibition strategies, as seen with agents like UNC1999 and Tulmimetostat, which target both EZH1 and EZH2. Given PRC2's multifaceted role in cancer biology, its inhibition represents a promising avenue for therapeutic intervention. The continued development of PRC2 inhibitors and exploration of their use in combination with standard chemotherapy or immunotherapy has great potential for improving patient outcomes in cancers driven by PRC2 dysregulation.
多梳抑制复合物2（PRC2）是通过组蛋白H3赖氨酸27位点的三甲基化来调控基因表达的关键因子。这种表观遗传修饰在维持细胞特性和控制细胞分化过程中发挥着至关重要的作用，而其失调与癌症进展密切相关。PRC2使肿瘤抑制基因沉默，促进细胞增殖、转移、上皮-间质转化以及癌症干细胞的可塑性。在包括淋巴瘤、乳腺癌和前列腺癌在内的多种癌症中，均观察到增强子结合蛋白2（EZH2）的过表达或功能获得性突变，这些变化促使肿瘤表现出侵袭性并产生耐药性。除EZH2外，其他PRC2组分，如胚胎外胚层发育蛋白（EED）和zeste基因抑制因子12，对于复合物的稳定性和功能也至关重要。特别是EED，它能增强EZH2的活性，并已成为一个治疗靶点。像MAK683和EED226这样的抑制剂会破坏EED维持PRC2活性的能力，从而降低H3K27me3水平并使肿瘤抑制基因重新激活。瓦美司他是一种同时抑制EZH2和EED的双靶点抑制剂，在弥漫性大B细胞淋巴瘤和小细胞肺癌等侵袭性癌症中已显示出有前景的结果，这凸显了靶向多个PRC2组分的治疗潜力。PRC2的作用不仅限于基因抑制，它还参与肿瘤的代谢重编程，调节糖酵解和脂质合成以促进癌症生长。此外，PRC2与化疗耐药相关，尤其是通过调节DNA损伤反应和免疫逃逸来实现。他泽司他是一种选择性EZH2抑制剂，在EZH2突变的癌症，如非霍奇金淋巴瘤和上皮样肉瘤中已显示出显著的临床疗效。然而，在某些癌症中，zeste基因增强子同源物1（EZH1）具有补偿功能，这就需要采用双重抑制策略，如UNC1999和图米司他等药物，它们同时靶向EZH1和EZH2。鉴于PRC2在癌症生物学中的多方面作用，对其进行抑制是一种很有前景的治疗干预途径。持续研发PRC2抑制剂，并探索将其与标准化疗或免疫疗法联合使用，对于改善由PRC2失调驱动的癌症患者的预后具有巨大潜力。
