Lin Lifeng, Shi Kaixuan, Zhou Shaoqing, Cai Mei-Chun, Zhang Caiyan, Sun Yunheng, Zang Jingyu, Cheng Lin, Ye Kaiyan, Ma Pengfei, Shen Peiye, Zhang Meiying, Cheng Yan, Qi Chunting, Li Ying, Yin Xia, Zheng Yiyan, Tan Li, Zhuang Guanglei, Zang Rongyu
Ovarian Cancer Program, Department of Gynecologic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.
State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Oncogene. 2022 Mar;41(12):1767-1779. doi: 10.1038/s41388-022-02210-3. Epub 2022 Feb 5.
Müllerian tissue-specific oncogenes, prototyped by PAX8, underlie ovarian tumorigenesis and represent unique molecular vulnerabilities. Further delineating such lineage-dependency factors and associated therapeutic implications would provide valuable insights into ovarian cancer biology and treatment. In this study, we identified SOX17 as a new lineage-survival master transcription factor, which shared co-expression pattern with PAX8 in epithelial ovarian carcinoma. Genetic disruption of SOX17 or PAX8 analogously inhibited neoplastic cell viability and downregulated a spectrum of lineage-related transcripts. Mechanistically, we showed that SOX17 physically interacted with PAX8 in cultured cell lines and clinical tumor specimens. The two nuclear proteins bound to overlapping genomic regions and regulated a common set of downstream genes, including those involved in cell cycle and tissue morphogenesis. In addition, we revealed that small-molecule inhibitors of transcriptional cyclin-dependent kinases (CDKs) effectively reduced SOX17 and PAX8 expression. ZSQ1722, a novel orally bioavailable CDK12/13 covalent antagonist, exerted potent anti-tumor activity in xenograft models. These findings shed light on an actionable lineage-survival transcriptional complex in ovarian cancer, and facilitated drug discovery by generating a serial of candidate compounds to pharmacologically target this difficult-to-treat malignancy.
以PAX8为代表的苗勒氏组织特异性癌基因是卵巢肿瘤发生的基础，并代表了独特的分子脆弱性。进一步阐明此类谱系依赖性因子及其相关治疗意义，将为卵巢癌生物学和治疗提供有价值的见解。在本研究中，我们鉴定出SOX17是一种新的谱系存活主转录因子，其在上皮性卵巢癌中与PAX8具有共表达模式。SOX17或PAX8的基因破坏类似地抑制肿瘤细胞活力，并下调一系列谱系相关转录本。从机制上讲，我们表明SOX17在培养的细胞系和临床肿瘤标本中与PAX8发生物理相互作用。这两种核蛋白结合到重叠的基因组区域，并调控一组共同的下游基因，包括那些参与细胞周期和组织形态发生的基因。此外，我们发现转录细胞周期蛋白依赖性激酶（CDK）的小分子抑制剂可有效降低SOX17和PAX8的表达。ZSQ1722是一种新型口服生物可利用的CDK12/13共价拮抗剂，在异种移植模型中发挥了强大的抗肿瘤活性。这些发现揭示了卵巢癌中一种可操作的谱系存活转录复合物，并通过生成一系列候选化合物来靶向这种难以治疗的恶性肿瘤，从而促进了药物发现。
