hnRNPL phase separation activates PIK3CB transcription and promotes glycolysis in ovarian cancer
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.
Authors
- Yifei Ren (ORCID: https://orcid.org/0000-0002-6081-7392)
- Fengjiang Qin (ORCID: https://orcid.org/0009-0003-8197-552X)
- Xinzhao Zuo (ORCID: https://orcid.org/0000-0003-2001-9932)
- Qinglv Wei (ORCID: https://orcid.org/0000-0002-6693-3917)
- Yan Tang (ORCID: https://orcid.org/0000-0002-6223-8423)
- Jing Xu (ORCID: https://orcid.org/0000-0001-8084-5609)
- Xin Luo (ORCID: https://orcid.org/0009-0008-5335-0713)
- Ping Yi (ORCID: https://orcid.org/0000-0001-7111-6308)
- Fatao Luo
- Chunming Cheng (ORCID: https://orcid.org/0000-0001-9036-1683)
- Yuya Wang
- Jie Xu (ORCID: https://orcid.org/0000-0002-5960-9174)
- Wei Wang (ORCID: https://orcid.org/0000-0002-2870-0733)
- Xiaoyi Liu (ORCID: https://orcid.org/0009-0006-5862-2031)
- Tao Liu (ORCID: https://orcid.org/0000-0001-9025-612X)
- Yang Yu (ORCID: https://orcid.org/0000-0002-4732-135X)
- Dan Yang (ORCID: https://orcid.org/0009-0003-0135-5110)
- Chenyue Yang
- Haocheng Wang (ORCID: https://orcid.org/0000-0001-8078-9475)
- Qingya Luo
Institutions
- Army Medical University (CN)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- Third People 's Hospital of Chongqing (CN)
- The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
- Southwest Hospital (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-24
- DOI
- https://doi.org/10.1038/s41467-025-60115-7
- Citations
- 1
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Natural Science Foundation of China
- Chongqing Medical University
- Natural Science Foundation of Chongqing
- Centre Scientifique et Technique du Bâtiment