Clear cell renal carcinoma essentially requires CDKL3 for oncogenesis
Clear cell renal cell carcinoma (ccRCC) is the predominant human renal cancer with surging incidence and fatality lately. Hyperactivation of hypoxia-inducible factor (HIF) and mammalian target of rapamycin (mTOR) signaling are the common signatures in ccRCC. Herein, we employed spontaneous ccRCC model to demonstrate the indispensability of an underappreciated Ser/Thr kinase, CDKL3, in the initiation and progression of ccRCC. Ablation of CDKL3 does not affect normal kidney, but abrogates Akt-mTOR hyperactivity and thoroughly prevents the formation and growth of the HIF-agitated ccRCC in vivo. Remarkable clinical correlations also supported the oncogenic role of CDKL3. Mechanism-wise, cytosolic CDKL3 unexpectedly behaves as the adaptor to physically potentiate mTORC2-dependent Akt activation without functioning through kinase activity. And mTORC2 can phosphorylate and stabilize CDKL3 to form a positive feedback loop to sustain the cancer-favored Akt-mTOR overactivation. Together, we revealed the pathological importance and molecular mechanism of CDKL3-mediated Akt-mTOR axis in ccRCC initiation and progression.
Authors
- Qiang Wang (ORCID: https://orcid.org/0000-0002-8735-8771)
- Kebang Hu (ORCID: https://orcid.org/0000-0003-2860-276X)
- Zhongqiu Pang
- Xuexin Li (ORCID: https://orcid.org/0000-0001-5824-9720)
- Aina He (ORCID: https://orcid.org/0000-0001-6442-3975)
- Shaoqin Zheng (ORCID: https://orcid.org/0000-0002-3027-7305)
- Ren Sheng (ORCID: https://orcid.org/0000-0002-2293-8986)
- Teng Fei (ORCID: https://orcid.org/0000-0002-3415-1654)
- Daming Gao (ORCID: https://orcid.org/0000-0003-4374-1055)
- Qing Han
- Liu Cao (ORCID: https://orcid.org/0000-0001-6471-1993)
- Yi Chen (ORCID: https://orcid.org/0000-0002-2310-1416)
- Xi Zhang (ORCID: https://orcid.org/0000-0002-0422-8980)
- Haijiao Zhang (ORCID: https://orcid.org/0000-0002-0749-9866)
- Xueling Yang (ORCID: https://orcid.org/0000-0001-7239-4297)
- W. X. Ding (ORCID: https://orcid.org/0009-0004-6707-8635)
- Labadze Ma
Institutions
- Northeastern University (US)
- Ministry of Education of the People's Republic of China (CN)
- Jilin University (CN)
- Chinese Academy of Sciences (CN)
- Karolinska Institutet (SE)
- Fourth Affiliated Hospital of China Medical University (CN)
- Center for Excellence in Molecular Cell Science (CN)
- First Hospital of Jilin University (CN)
- Shanghai Sixth People's Hospital (CN)
- Columbia University (US)
- South China University of Technology (CN)
- China Medical University (CN)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-02-12
- DOI
- https://doi.org/10.1073/pnas.2415244122
- Citations
- 3
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- National Natural Science Foundation of China
- Liaoning Revitalization Talents Program
- Foundation for Fundamental Research of China