Cleavage and Polyadenylation Specific Factor 1 Promotes Tumor Progression via Alternative Polyadenylation and Splicing in Hepatocellular Carcinoma

Shi-Lu Chen; Zhong-Xu Zhu; Xia Yang; Li-Li Liu; Yang-Fan He; Ming-Ming Yang; Xin-Yuan Guan; Xin Wang; Jing-Ping Yun

doi:10.3389/fcell.2021.616835

Cleavage and Polyadenylation Specific Factor 1 Promotes Tumor Progression via Alternative Polyadenylation and Splicing in Hepatocellular Carcinoma

Front Cell Dev Biol. 2021 Mar 4:9:616835. doi: 10.3389/fcell.2021.616835. eCollection 2021.

Authors

Shi-Lu Chen^{1

2}, Zhong-Xu Zhu³, Xia Yang^{1

2}, Li-Li Liu^{1

2}, Yang-Fan He^{1

2}, Ming-Ming Yang^{1

2}, Xin-Yuan Guan¹, Xin Wang^{3

4}, Jing-Ping Yun^{1

2}

Affiliations

¹ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
² Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
³ Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
⁴ Key Laboratory of Biochip Technology, Biotech and Health Centre, Shenzhen Research Institute, City University of Hong Kong, Shenzhen, China.

Abstract

Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism required for cleavage and polyadenylation (CPA) of the 3' untranslated region (3' UTR) of mRNAs. Several aberrant APA events have been reported in hepatocellular carcinoma (HCC). However, the regulatory mechanisms underlying APA remain unclear. In this study, we found that the expression of cleavage and polyadenylation specific factor 1 (CPSF1), a major component of the CPA complex, was significantly increased in HCC tissues and correlated with unfavorable survival outcomes. Knockdown of CPSF1 inhibited HCC cell proliferation and migration, whereas overexpression of CPSF1 caused the opposite effect. Based on integrative analysis of Iso-Seq and RNA-seq data from HepG2.2.15 cells, we identified a series of transcripts with differential 3' UTR lengths following the knockdown of CPSF1. These transcripts were related to the biological functions of gene transcription, cytoskeleton maintenance, and endomembrane system transportation. Moreover, knockdown of CPSF1 induced an increase in alternative splicing (AS) events in addition to APA. Taken together, this study provides new insights into our understanding of the post-transcriptional regulatory mechanisms in HCC and implies that CPSF1 may be a potential prognostic biomarker and therapeutic target for HCC.

Keywords: alternative polyadenylation; alternative splicing; cleavage and polyadenylation; cleavage and polyadenylation specific factor 1; hepatocellular carcinoma.