Mutually exclusive acetylation and ubiquitylation of the splicing factor SRSF5 control tumor growth

Yuhan Chen, Qingyang Huang, Wen Liu, Qiong Zhu, Chun-Ping Cui, Liang Xu, Xing Guo, Ping Wang, Jingwen Liu, Guanglong Dong, Wenyi Wei, Cui Hua Liu, Zhichun Feng, Fuchu He () and Lingqiang Zhang ()
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Yuhan Chen: Beijing Institute of Lifeomics
Qingyang Huang: Beijing Institute of Lifeomics
Wen Liu: Beijing Institute of Lifeomics
Qiong Zhu: Beijing Institute of Lifeomics
Chun-Ping Cui: Beijing Institute of Lifeomics
Liang Xu: Beijing Institute of Radiation Medicine
Xing Guo: Beijing Institute of Radiation Medicine
Ping Wang: Tongji University
Jingwen Liu: Chinese People’s Liberation Army General Hospital
Guanglong Dong: Chinese People’s Liberation Army General Hospital
Wenyi Wei: Harvard Medical School
Cui Hua Liu: Chinese Academy of Sciences
Zhichun Feng: National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing Key Laboratory of Pediatric Organ Failure
Fuchu He: Beijing Institute of Lifeomics
Lingqiang Zhang: Beijing Institute of Lifeomics

Nature Communications, 2018, vol. 9, issue 1, 1-21

Abstract: Abstract Most tumor cells take up more glucose than normal cells. Splicing dysregulation is one of the molecular hallmarks of cancer. However, the role of splicing factor in glucose metabolism and tumor development remains poorly defined. Here, we show that upon glucose intake, the splicing factor SRSF5 is specifically induced through Tip60-mediated acetylation on K125, which antagonizes Smurf1-mediated ubiquitylation. SRSF5 promotes the alternative splicing of CCAR1 to produce CCAR1S proteins, which promote tumor growth by enhancing glucose consumption and acetyl-CoA production. Conversely, upon glucose starvation, SRSF5 is deacetylated by HDAC1, and ubiquitylated by Smurf1 on the same lysine, resulting in proteasomal degradation of SRSF5. The CCAR1L proteins accumulate to promote apoptosis. Importantly, SRSF5 is hyperacetylated and upregulated in human lung cancers, which correlates with increased CCAR1S expression and tumor progression. Thus, SRSF5 responds to high glucose to promote cancer development, and SRSF5–CCAR1 axis may be valuable targets for cancer therapeutics.

Date: 2018
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DOI: 10.1038/s41467-018-04815-3

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