C6orf223 promotes colorectal cancer growth and metastasis by facilitating PRMT5-MEP50 multiprotein complex assembling
Protein arginine methyltransferase 5 (PRMT5) complexes with methylosome protein 50 (MEP50) play crucial roles in tumor progress. However, the regulatory mechanism of governing the PRMT5-MEP50 hetero-octameric complex remains unclear. Here, we demonstrate that C6orf223, to our knowledge an uncharacterized protein, facilitates PRMT5-MEP50 multiprotein complex assembling, thereby promoting colorectal cancer (CRC) growth and metastasis. C6orf223 forms dimers through disulfide bonds, with its N-terminal arginine-enriched region binding to the C-terminal negatively charged groove of PRMT5, thus stabilizing PRMT5-MEP50 multiprotein and enhancing PRMT5 methyltransferase activity. Consequently, PRMT5-mediated H4R3me2s substantially decreases the expression of the tumor suppressor GATA5, leading to the upregulation of multiple oncogenic target genes including WWTR1, FGFR1, and CLU. Targeting C6orf223 using siRNAs encapsulated in ferritin protein shells effectively suppresses CRC tumor growth and metastasis. Collectively, our findings characterize the role of C6orf223 in facilitating PRMT5-MEP50 hetero-octameric complex assembling and suggest that C6orf223 could serve as a potential therapeutic target for CRC.
Authors
- Bing Zhou (ORCID: https://orcid.org/0000-0002-6585-9284)
- Pengcheng Bu (ORCID: https://orcid.org/0000-0002-3208-0354)
- Furong Bai (ORCID: https://orcid.org/0000-0002-5312-5021)
- Peng Zhang (ORCID: https://orcid.org/0000-0002-5835-4034)
- Jizhong Lou (ORCID: https://orcid.org/0000-0003-4031-6125)
- Kelong Fan (ORCID: https://orcid.org/0000-0001-6285-1933)
- Yiliang Jin (ORCID: https://orcid.org/0000-0003-3409-3287)
- Junfeng Du (ORCID: https://orcid.org/0000-0002-8482-4271)
- Meiying Xue
- Pu Gao (ORCID: https://orcid.org/0000-0002-5328-9755)
- Yunhe An (ORCID: https://orcid.org/0000-0003-4117-1407)
- Peng Wang (ORCID: https://orcid.org/0000-0003-1845-7589)
- Fei Zhang (ORCID: https://orcid.org/0000-0002-4675-7207)
- Yong Zhang (ORCID: https://orcid.org/0000-0002-5831-637X)
- Zhenhua Wu (ORCID: https://orcid.org/0000-0003-4552-883X)
- Jinbo Liu (ORCID: https://orcid.org/0000-0003-2022-7029)
- Huiyun Cai
- Han Feng (ORCID: https://orcid.org/0000-0002-2386-8799)
- Yufeng Qiao
- Guizhi Shi
- Yaxin Hou (ORCID: https://orcid.org/0000-0002-1330-6506)
Institutions
- Capital Medical University (CN)
- Chinese Academy of Sciences (CN)
- Chinese PLA General Hospital (CN)
- Institute of Biophysics (CN)
- Beijing Children’s Hospital (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Beijing Academy of Science and Technology (CN)
- University of Chinese Academy of Sciences (CN)
- Institute of Zoology (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-10-14
- DOI
- https://doi.org/10.1172/jci186052
- Citations
- 1
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.81