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SOX17 and PAX8 constitute an actionable lineage-survival transcriptional complex in ovarian cancer

Oncogene volume 41, pages 1767–1779 (2022)Cite this article

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Abstract

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.

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Fig. 1: SOX17 and PAX8 display Müllerian lineage-specific co-expression.
Fig. 2: SOX17 and PAX8 are indispensable to a subset of ovarian cancer.
Fig. 3: SOX17 and PAX8 form a nuclear protein complex.
Fig. 4: Integrated analyses identify common target genes of SOX17 and PAX8.
Fig. 5: Transcriptional CDK inhibitors ablate SOX17 and PAX8 expression.
Fig. 6: Novel covalent CDK12/13 inhibitors downregulate SOX17 and PAX8.
Fig. 7: Orally bioavailable ZSQ1722 elicits potent anticancer effects in vivo.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81972429 to RZ; 81922047 and 82172596 to GZ; 82173077 to XY; 82173111 to MZ), the Science and Technology Commission of Shanghai Municipality (18140902300 to RZ; 18JC1420500 to LT), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20161313 to GZ), Shanghai Municipal Science and Technology Major Project (Grant No. 2019SHZDZX02 to LT), Shanghai Natural Science Foundation (20ZR1433100 to XY), Shanghai Shenkang Hospital Development Center (SHDC2020CR3057B to XY), Shanghai Collaborative Innovation Center for Translational Medicine (TM202004 to XY), Beijing Kuanghua foundation for the development of Chinese and Western Medicine (BKF) (KH-2021-LLZX-018 to XY), Shanghai Jiao Tong University School of Medicine (YG2021GD02 and TMSK-2021-207 to XY), the grants from Shanghai Key Laboratory of Gynecologic Oncology (FKZL-2018-02 to PM).

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  1. These authors contributed equally: Lifeng Lin, Kaixuan Shi, Shaoqing Zhou, Mei-Chun Cai.

Authors and Affiliations

  1. Ovarian Cancer Program, Department of Gynecologic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China

    Lifeng Lin, Yiyan Zheng & Rongyu Zang

  2. 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

    Kaixuan Shi, Yunheng Sun, Jingyu Zang, Lin Cheng, Kaiyan Ye, Pengfei Ma, Peiye Shen, Meiying Zhang, Xia Yin & Guanglei Zhuang

  3. Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Kaixuan Shi, Yunheng Sun, Jingyu Zang, Lin Cheng, Kaiyan Ye, Pengfei Ma, Peiye Shen, Meiying Zhang, Xia Yin & Guanglei Zhuang

  4. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Shaoqing Zhou, Yan Cheng, Chunting Qi, Ying Li & Li Tan

  5. University of Chinese Academy of Sciences, Beijing, China

    Shaoqing Zhou & Li Tan

  6. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Mei-Chun Cai & Caiyan Zhang

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Contributions

RZ, GZ, and LT conceptualized the study. LL, KS, and SZ carried out most of the experiments and analyzed data. CZ, YS, LC, KY, PS, MZ, YC, and CQ participated in experiment conduction. MCC and JZ performed the bioinformatics analyses. PM, YL, XY, and YZ provided technical or material support. GZ and LL drafted the paper. All the authors edited and approved the paper.

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Correspondence to Li Tan, Guanglei Zhuang or Rongyu Zang.

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Lin, L., Shi, K., Zhou, S. et al. SOX17 and PAX8 constitute an actionable lineage-survival transcriptional complex in ovarian cancer. Oncogene 41, 1767–1779 (2022). https://doi.org/10.1038/s41388-022-02210-3

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