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Nat Commun. 2018 Jun 25;9(1):2464. doi: 10.1038/s41467-018-04815-3.

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

Chen Y1,2,3, Huang Q1,2, Liu W1,2, Zhu Q1,2, Cui CP1,2, Xu L2,4, Guo X2,5, Wang P6, Liu J7, Dong G7, Wei W8, Liu CH9, Feng Z3, He F10,11, Zhang L12,13,14.

Author information

1
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China.
2
Department of Genomics and Proteomics, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
3
Affiliated BaYi Children's Hospital, PLA Army General Hospital, National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing Key Laboratory of Pediatric Organ Failure, Beijing, 100700, China.
4
Department of Biochemistry and Molecular Biology, Anhui Medical University, Hefei, 230032, Anhui, China.
5
Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
6
Department of Central Laboratory, Shanghai Tenth People's Hospital, School of Life Science and Technology, Tongji University, Shanghai, 200072, China.
7
Department of General Surgery, Chinese People's Liberation Army General Hospital, Beijing, 100853, China.
8
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA.
9
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
10
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China. hefc@nic.bmi.ac.cn.
11
Department of Genomics and Proteomics, Beijing Institute of Radiation Medicine, Beijing, 100850, China. hefc@nic.bmi.ac.cn.
12
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China. zhanglq@nic.bmi.ac.cn.
13
Department of Genomics and Proteomics, Beijing Institute of Radiation Medicine, Beijing, 100850, China. zhanglq@nic.bmi.ac.cn.
14
School of Life Science, Jiangsu Normal University, Xuzhou, 221116, Jiangsu, China. zhanglq@nic.bmi.ac.cn.

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.

PMID:
29942010
PMCID:
PMC6018636
DOI:
10.1038/s41467-018-04815-3
[Indexed for MEDLINE]
Free PMC Article

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