Sarwar Sadia, Alamro Abir, Huq Fazlul, Alghamdi Amani
Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.
Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.
Front Genet. 2022 Jul 8;13:812077. doi: 10.3389/fgene.2022.812077. eCollection 2022.
Ovarian cancer is one of the most lethal malignancies. The population at the risk is continually on the rise due to the acquired drug resistance, high relapse rate, incomplete knowledge of the etiology, cross-talk with other gynecological malignancies, and diagnosis at an advanced stage. Most ovarian tumors are thought to arise in surface epithelium somehow in response to changes in the hormonal environment. Prolonged treatment with hormone replacement therapy (HRT) is also considered a contributing factor. Estrogens influence the etiology and progression of the endocrine/hormone-responsive cancers in a patient-specific manner. The concept of hormonal manipulations got attention during the last half of the 20th century when tamoxifen was approved by the FDA as the first selective estrogen receptor modulator (SERM). Endocrine therapy that has been found to be effective against breast cancer can be an option for ovarian cancer. It is now established that global changes in the epigenetic landscape are not only the hallmark of tumor development but also contribute to the development of resistance to hormone therapy. A set of functionally related genes involved in epigenetic reprogramming are controlled by specific transcription factors (TFs). Thus, the activities of TFs mediate important mechanisms through which epigenetic enzymes and co-factors modify chromatin for the worst outcome in a site-specific manner. Furthermore, the role of epigenetic aberrations involving histone modifications is established in ovarian cancer pathogenesis. This review aims to provide insights on the role of key epigenetic determinants of response as well as resistance to the hormone therapy, the current status of research along with its limitations, and future prospects of epigenetic agents as biomarkers in early diagnosis, prognosis, and personalized treatment strategies. Finally, the possibility of small phytoestrogenic molecules in combination with immunotherapy and epi-drugs targeting ovarian cancer has been discussed.
卵巢癌是最致命的恶性肿瘤之一。由于获得性耐药、高复发率、病因认识不全面、与其他妇科恶性肿瘤的相互作用以及晚期诊断等原因，高危人群数量持续上升。大多数卵巢肿瘤被认为是表面上皮细胞以某种方式对激素环境变化作出反应而产生的。长期使用激素替代疗法（HRT）也被认为是一个促成因素。雌激素以患者特异性方式影响内分泌/激素反应性癌症的病因和进展。20世纪后半叶，当他莫昔芬被美国食品药品监督管理局（FDA）批准为首个选择性雌激素受体调节剂（SERM）时，激素操纵的概念受到了关注。已发现对乳腺癌有效的内分泌疗法可能是卵巢癌的一种选择。现在已经确定，表观遗传景观的全局变化不仅是肿瘤发展的标志，而且还导致对激素疗法产生耐药性。一组参与表观遗传重编程的功能相关基因由特定转录因子（TFs）控制。因此，TFs的活性介导了重要机制，通过这些机制表观遗传酶和辅助因子以位点特异性方式修饰染色质，导致最坏的结果。此外，涉及组蛋白修饰的表观遗传异常在卵巢癌发病机制中的作用已得到证实。本综述旨在深入探讨关键表观遗传决定因素在激素疗法反应及耐药中的作用、当前研究现状及其局限性，以及表观遗传药物作为早期诊断、预后和个性化治疗策略生物标志物的未来前景。最后，还讨论了小植物雌激素分子与免疫疗法及靶向卵巢癌的表观遗传药物联合使用的可能性。
