Ramadoss S, Sen S, Ramachandran I, Roy S, Chaudhuri G, Farias-Eisner R
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
Department of Endocrinology, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600 113, Tamil Nadu, India.
Oncogene. 2017 Mar;36(11):1537-1545. doi: 10.1038/onc.2016.320. Epub 2016 Oct 3.
Ovarian cancer is the leading cause of death among all gynecological malignancies due to the development of acquired chemoresistance and disease relapse. Although the role of cancer stem cells (CSCs), a subset of tumor cells with the self-renewal and differentiation capabilities, in therapeutic resistance is beginning to be better understood, the significance of epigenetic regulatory mechanisms responsible for integrating the stemness with drug resistance remain poorly understood. Here we identified that lysine demethylase KDM3A as a critical regulator of ovarian cancer stemness and cisplatin resistance by inducing the expressions of pluripotent molecules Sox2 and Nanog and anti-apoptotic B-cell lymphoma 2 (Bcl-2), respectively. In addition, KDM3A induces ovarian cancer growth while antagonizing cellular senescence by repressing the expression of cyclin-dependent kinase inhibitor, p21. The underlying mechanism of the noted biological processes include KDM3A-mediated stimulation of Sox2 expression, and demethylating p53 protein and consequently, modulating its target genes such as Bcl-2 and p21 expression. Consistently, KDM3A depletion inhibited the growth of subcutaneously implanted cisplatin-resistant human ovarian cancer cells in athymic nude mice. Moreover, KDM3A is abundantly expressed and positively correlated with Sox2 expression in human ovarian cancer tissues. In brief, our findings reveal a novel mechanism by which KDM3A promotes ovarian CSCs, proliferation and chemoresistance and thus, highlights the significance of KDM3A as a novel therapeutic target for resistant ovarian cancer.
由于获得性化疗耐药性的发展和疾病复发，卵巢癌是所有妇科恶性肿瘤中导致死亡的主要原因。尽管癌症干细胞（CSCs）作为具有自我更新和分化能力的肿瘤细胞亚群，在治疗耐药中的作用开始得到更好的理解，但负责整合干性与耐药性的表观遗传调控机制的重要性仍知之甚少。在这里，我们发现赖氨酸去甲基化酶KDM3A分别通过诱导多能分子Sox2和Nanog以及抗凋亡的B细胞淋巴瘤2（Bcl-2）的表达，成为卵巢癌干性和顺铂耐药的关键调节因子。此外，KDM3A通过抑制细胞周期蛋白依赖性激酶抑制剂p21的表达来诱导卵巢癌生长，同时拮抗细胞衰老。上述生物学过程的潜在机制包括KDM3A介导的对Sox2表达的刺激，以及使p53蛋白去甲基化，从而调节其靶基因如Bcl-2和p21的表达。一致地，KDM3A的缺失抑制了无胸腺裸鼠皮下植入的顺铂耐药人卵巢癌细胞的生长。此外，KDM3A在人卵巢癌组织中大量表达，且与Sox2表达呈正相关。简而言之，我们的研究结果揭示了一种新机制，通过该机制KDM3A促进卵巢癌干细胞、增殖和化疗耐药，因此，突出了KDM3A作为耐药卵巢癌新治疗靶点的重要性。
