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 8

Identification of GATA5 target genes in response to C6orf223-mediated CRC growth and metastasis.

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Identification of GATA5 target genes in response to C6orf223-mediated CR...
(A) Binding motif of GATA5 analyzed by JASPAR. (B) Schematic of the strategy to screen the target genes of GATA5. (C) ChIP-qPCR showing the enrichment of GATA5 binding in the promoter of the putative target genes in HT29 cells with ectopic GATA5 expression. Data are shown as the mean ± SD of 3 independent repeated experiments. P value was calculated by 2-way ANOVA (*P < 0.05, **P < 0.01). (D) Luciferase reporter assay of the putative GATA5 target genes. HEK293T cells were transfected with luciferase vector containing promoter sequence of the putative GATA5 target genes together with GATA5 plasmids or empty vector, followed by luciferase activity measurement. Data are shown as the mean ± SD of 3 independent repeated experiments. P value was calculated by 2-way ANOVA (**P < 0.01, ***P < 0.001). (E) Western blot showing the expression levels of FGFR1, CLU, and WWTR1 in HT29 cells with ectopic expression of C6orf223 or C6orf223 together with GATA5. (F and G) Quantification (F) and representative IHC image (G) showing the expression level of C6orf223, GATA5, WWTR1, FGFR1, and CLU in primary cecum tumors from mice orthotopically injected with HT29 cells. Scale bar: 100 μm. Data are shown as the mean ± SEM of 5 mice per group. P value was calculated by 2-way ANOVA (NS; *P < 0.05, **P < 0.01, ***P < 0.001).