C6orf223 promotes colorectal cancer growth and metastasis by facilitating PRMT5-MEP50 multiprotein complex assembling
Yufeng Qiao, Zhenzhen Wu, Peng Wang, Yiliang Jin, Furong Bai, Fei Zhang, Yunhe An, Meiying Xue, Han Feng, Yong Zhang, Yaxin Hou, Junfeng Du, Huiyun Cai, Guizhi Shi, Bing Zhou, Pu Gao, Jizhong Lou, Peng Zhang, Kelong Fan, Jinbo Liu, Pengcheng Bu
Yufeng Qiao, Zhenzhen Wu, Peng Wang, Yiliang Jin, Furong Bai, Fei Zhang, Yunhe An, Meiying Xue, Han Feng, Yong Zhang, Yaxin Hou, Junfeng Du, Huiyun Cai, Guizhi Shi, Bing Zhou, Pu Gao, Jizhong Lou, Peng Zhang, Kelong Fan, Jinbo Liu, Pengcheng Bu
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Research Article Cell biology Oncology

C6orf223 promotes colorectal cancer growth and metastasis by facilitating PRMT5-MEP50 multiprotein complex assembling

Abstract

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

Yufeng Qiao, Zhenzhen Wu, Peng Wang, Yiliang Jin, Furong Bai, Fei Zhang, Yunhe An, Meiying Xue, Han Feng, Yong Zhang, Yaxin Hou, Junfeng Du, Huiyun Cai, Guizhi Shi, Bing Zhou, Pu Gao, Jizhong Lou, Peng Zhang, Kelong Fan, Jinbo Liu, Pengcheng Bu

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Figure 1

Increased PRMT5-MEP50 hetero-octamer level and PRMT5 methyltransferase activity in CRC liver metastases.

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Increased PRMT5-MEP50 hetero-octamer level and PRMT5 methyltransferase a...
(A) Comparison of the levels of PRMT5 between pericarcinomatous tissue (normal, n = 377), primary CRC (tumor, n = 1,450) and liver metastatic samples (metastasis, n = 99) using TNMplot. P value was calculated by Kruskal-Wallis test. (B and C) Representative IHC images (B) and quantification (C) of PRMT5 levels on a tissue microarray containing 13 paired pericarcinomatous tissue samples, primary CRC and liver metastatic samples, and 12 paired primary colon tumor and liver metastatic samples. Upper scale bar: 500 μm; lower scale bar: 100 μm. P value was calculated by χ2 test (NS, **P < 0.01). (D) Western blot showing SDMA and PRMT5 levels in paired primary CRC (P) and liver metastatic samples (M). (E) Schematic of the CRC orthotopic mouse model. (F) Representative bright-field images (right) and quantification (left) of the metastases on the liver surface in NCG mice with cecum injection of HT29 cells stably expressing PRMT5 or not. Data are shown as the mean ± SEM of 5 mice per group. P value was calculated by 2-tailed paired Student’s t test (**P < 0.01). (G) Western blot showing SDMA, H4R3me2s and PRMT5 levels in paired primary tumor (P) and liver metastasis (M) of NCG mice with cecum injection of HT29 cells stably expressing PRMT5 or not. (H) Schematic of the process of PRMT5 monomer and MEP50 monomer forming PRMT5-MEP50 hetero-octamer. MEP50 monomers are colored pink. N-term, middle; C-term of PRMT5 are colored blue, yellow, and green, respectively. (I) Blue native PAGE showing the levels of PRMT5 hetero-octamer in paired primary tumor (P) and liver metastasis (M) of NCG mice with cecum injection of HT29 cells stably expressing PRMT5 or not. (J) Blue native PAGE showing the levels of PRMT5 hetero-octamer in paired primary tumor (P) and liver metastases (M) of patients with CRC.