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.
Highlights
Most tumor cells take up more glucose than normal cells
SRSF5 is stabilized at high glucose to promote tumorigenesis
To investigate whether certain splicing factors respond to glucose intake, we screened all 12 members of SR-splicing factors (SRSFs) family and examined their expression levels in A549 cells supplemented with different concentrations of glucose
Summary
Most tumor cells take up more glucose than normal cells. Splicing dysregulation is one of the molecular hallmarks of cancer. SRSF5 promotes the alternative splicing of CCAR1 to produce CCAR1S proteins, which promote tumor growth by enhancing glucose consumption and acetyl-CoA production. 6 Department of Central Laboratory, Shanghai Tenth People’s Hospital, School of Life Science and Technology, Tongji University, Shanghai 200072, China. 10 School of Life Science, Jiangsu Normal University, Xuzhou, 221116 Jiangsu, China These authors contributed : Qingyang Huang, Wen Liu. Correspondence and requests for materials should be addressed to Emerging as one of the most prevalent mechanisms of gene regulation, alternative splicing (AS) plays a vital role in the intricate regulation of protein function and splicing dysregulation is closely associated with human cancers[1]. The role of splicing factors in glucose metabolism and tumor development still remains poorly defined
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