PUF60 promotes cell cycle and lung cancer progression by regulating alternative splicing of CDC25C

Nan Xu; Yunpeng Ren; Yufang Bao; Xianfeng Shen; Jiahui Kang; Ning Wang; Zixian Wang; Xinlu Han; Zhen Li; Ji Zuo; Gong-Hong Wei; Zefeng Wang; Wei-Xing Zong; Wen Liu; Gangcai Xie; Yongbo Wang

doi:10.1016/j.celrep.2023.113041

PUF60 promotes cell cycle and lung cancer progression by regulating alternative splicing of CDC25C

Cell Rep. 2023 Sep 26;42(9):113041. doi: 10.1016/j.celrep.2023.113041. Epub 2023 Sep 8.

Authors

Nan Xu¹, Yunpeng Ren¹, Yufang Bao¹, Xianfeng Shen¹, Jiahui Kang², Ning Wang³, Zixian Wang⁴, Xinlu Han¹, Zhen Li¹, Ji Zuo¹, Gong-Hong Wei⁴, Zefeng Wang³, Wei-Xing Zong⁵, Wen Liu¹, Gangcai Xie⁶, Yongbo Wang⁷

Affiliations

¹ Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
² Institute of Reproductive Medicine, Medical School, Nantong University, Qixiu Road 19, Nantong 226001, China.
³ Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.
⁴ MOE Key Laboratory of Metabolism and Molecular Medicine & Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai 200032, China.
⁵ Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, NJ 08854, USA.
⁶ Institute of Reproductive Medicine, Medical School, Nantong University, Qixiu Road 19, Nantong 226001, China. Electronic address: gangcai@ntu.edu.cn.
⁷ Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Minhang Hospital & Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: wangyongbo@fudan.edu.cn.

PMID: 37682709
DOI: 10.1016/j.celrep.2023.113041

Abstract

Alternative splicing (AS) has been implicated in cell cycle regulation and cancer, but the underlying mechanisms are poorly understood. The poly(U)-binding splicing factor 60 (PUF60) is essential for embryonic development and is overexpressed in multiple types of cancer. Here, we report that PUF60 promotes mitotic cell cycle and lung cancer progression by controlling AS of the cell division cycle 25C (CDC25C). Systematic analysis of splicing factors deregulated in lung adenocarcinoma (LUAD) identifies that elevated copy number and expression of PUF60 correlate with poor prognosis. PUF60 depletion inhibits LUAD cell-cycle G2/M transition, cell proliferation, and tumor development. Mechanistically, PUF60 knockdown leads to exon skipping enriched in mitotic cell cycle genes, including CDC25C. Exon 3 skipping in the full-length CDC25C results in nonsense-mediated mRNA decay and a decrease of CDC25C protein, thereby inhibiting cell proliferation. This study establishes PUF60 as a cell cycle regulator and an oncogenic splicing factor in lung cancer.

Keywords: CDC25C; CP: Cancer; PUF60; alternative splicing; cell cycle; lung cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung* / genetics
Alternative Splicing / genetics
Cell Cycle / genetics
Cell Division
Cell Line, Tumor
Humans
Lung Neoplasms* / genetics
RNA Splicing Factors / genetics
RNA Splicing Factors / metabolism
cdc25 Phosphatases / genetics
cdc25 Phosphatases / metabolism

Substances

cdc25 Phosphatases
CDC25C protein, human
RNA Splicing Factors
poly-U binding splicing factor 60KDa

Grants and funding

R01 CA129536/CA/NCI NIH HHS/United States