CPSF6 regulates alternative polyadenylation and proliferation of cancer cells through phase separation
Susu Liu,
Runze Wu,
Liutao Chen,
Ke Deng,
Xin Ou,
Xin Lu,
Mengxia Li,
Chao Liu,
Shangwu Chen,
Yonggui Fu,
Anlong Xu
Affiliations
Susu Liu
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China
Runze Wu
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China
Liutao Chen
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China
Ke Deng
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China
Xin Ou
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China
Xin Lu
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China
Mengxia Li
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China
Chao Liu
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China
Shangwu Chen
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China
Yonggui Fu
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China; Corresponding author
Anlong Xu
State Key Laboratory for Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, P.R. China; School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, P.R. China; Corresponding author
Summary: Cancer cells usually exhibit shortened 3′ untranslated regions (UTRs) due to alternative polyadenylation (APA) to promote cell proliferation and migration. Upregulated CPSF6 leads to a systematic prolongation of 3′ UTRs, but CPSF6 expression in tumors is typically higher than that in healthy tissues. This contradictory observation suggests that it is necessary to investigate the underlying mechanism by which CPSF6 regulates APA switching in cancer. Here, we find that CPSF6 can undergo liquid-liquid phase separation (LLPS), and elevated LLPS is associated with the preferential usage of the distal poly(A) sites. CLK2, a kinase upregulated in cancer cells, destructs CPSF6 LLPS by phosphorylating its arginine/serine-like domain. The reduction of CPSF6 LLPS can lead to a shortened 3′ UTR of cell-cycle-related genes and accelerate cell proliferation. These results suggest that CPSF6 LLPS, rather than its expression level, may be responsible for APA regulation in cancer cells.
