State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center of Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 100850, China.
Department of Genomics and Proteomics, Beijing Institute of Radiation Medicine, Beijing, 100850, China.
Nat Commun. 2018 Jun 25;9(1):2464. doi: 10.1038/s41467-018-04815-3.
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.
大多数肿瘤细胞比正常细胞吸收更多的葡萄糖。剪接失调是癌症的分子标志之一。然而，剪接因子在葡萄糖代谢和肿瘤发展中的作用仍未得到明确界定。在这里，我们表明，在摄入葡萄糖后，剪接因子 SRSF5 通过 Tip60 介导的 K125 乙酰化被特异性诱导，这拮抗了 Smurf1 介导的泛素化。SRSF5 促进 CCAR1 的选择性剪接产生 CCAR1S 蛋白，通过增强葡萄糖消耗和乙酰辅酶 A 生成促进肿瘤生长。相反，在葡萄糖饥饿时，SRSF5 被 HDAC1 去乙酰化，在同一赖氨酸上被 Smurf1 泛素化，导致 SRSF5 的蛋白酶体降解。CCAR1L 蛋白积累以促进细胞凋亡。重要的是，SRSF5 在人类肺癌中高度乙酰化和上调，这与 CCAR1S 表达增加和肿瘤进展相关。因此，SRSF5 响应高葡萄糖以促进癌症发展，SRSF5-CCAR1 轴可能是癌症治疗的有价值靶点。
