hnRNPL phase separation activates PIK3CB transcription and promotes glycolysis in ovarian cancer

Fengjiang Qin, Yuya Wang, Chenyue Yang, Yifei Ren, Qinglv Wei, Yan Tang, Jie Xu, Haocheng Wang, Fatao Luo, Qingya Luo, Xin Luo, Xiaoyi Liu, Dan Yang, Xinzhao Zuo, Yu Yang, Chunming Cheng, Jing Xu, Wei Wang, Tao Liu () and Ping Yi ()
Additional contact information
Fengjiang Qin: The Third Affiliated Hospital of Chongqing Medical University
Yuya Wang: The Third Affiliated Hospital of Chongqing Medical University
Chenyue Yang: The Third Affiliated Hospital of Chongqing Medical University
Yifei Ren: The Third Affiliated Hospital of Chongqing Medical University
Qinglv Wei: The Third Affiliated Hospital of Chongqing Medical University
Yan Tang: The Third Affiliated Hospital of Chongqing Medical University
Jie Xu: The Third Affiliated Hospital of Chongqing Medical University
Haocheng Wang: The Third Affiliated Hospital of Chongqing Medical University
Fatao Luo: The First Affiliated Hospital of Chongqing Medical University
Qingya Luo: Southwest Hospital, Army Medical University
Xin Luo: The Third Affiliated Hospital of Chongqing Medical University
Xiaoyi Liu: The Third Affiliated Hospital of Chongqing Medical University
Dan Yang: The Third Affiliated Hospital of Chongqing Medical University
Xinzhao Zuo: The Third Affiliated Hospital of Chongqing Medical University
Yu Yang: The Third Affiliated Hospital of Chongqing Medical University
Chunming Cheng: The Ohio State University
Jing Xu: The Third Affiliated Hospital of Chongqing Medical University
Wei Wang: Chongqing Medical University
Tao Liu: The Third Affiliated Hospital of Chongqing Medical University
Ping Yi: The First Affiliated Hospital of Chongqing Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Ovarian cancer has the highest mortality rate among gynecologic tumors worldwide, with unclear underlying mechanisms of pathogenesis. RNA-binding proteins (RBPs) primarily direct post-transcriptional regulation through modulating RNA metabolism. Recent evidence demonstrates that RBPs are also implicated in transcriptional control. However, the role and mechanism of RBP-mediated transcriptional regulation in tumorigenesis remain largely unexplored. Here, we show that the RBP heterogeneous ribonucleoprotein L (hnRNPL) interacts with chromatin and regulates gene transcription by forming phase-separated condensates in ovarian cancer. hnRNPL phase separation activates PIK3CB transcription and glycolysis, thus promoting ovarian cancer progression. Notably, we observe that the PIK3CB promoter is transcribed to produce a non-coding RNA which interacts with hnRNPL and promotes hnRNPL condensation. Furthermore, hnRNPL is significantly amplified in ovarian cancer, and its high expression predicts poor prognosis for ovarian cancer patients. By using cell-derived xenograft and patient-derived organoid models, we show that hnRNPL knockdown suppresses ovarian tumorigenesis. Together, our study reveals that phase separation of the chromatin-associated RBP hnRNPL promotes PIK3CB transcription and glycolysis to facilitate tumorigenesis in ovarian cancer. The formed hnRNPL-PIK3CB-AKT axis depending on phase separation can serve as a potential therapeutic target for ovarian cancer.

Date: 2025
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DOI: 10.1038/s41467-025-60115-7

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