Department of Human Anatomy, Histology and Embryology, MOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, 100191, China.
MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
Sci China Life Sci. 2022 Jan;65(1):129-141. doi: 10.1007/s11427-020-1914-3. Epub 2021 Apr 29.
Large tumor suppressor 1 (LATS1) is the key kinase controlling activation of Hippo signalling pathway. Post-translational modifications of LATS1 modulate its kinase activity. However, detailed mechanism underlying LATS1 stability and activation remains elusive. Here we report that LATS1 is acetylated by acetyltransferase CBP at K751 and is deacetylated by deacetylases SIRT3 and SIRT4. Acetylation at K751 stabilized LATS1 by decreasing LATS1 ubiquitination and inhibited LATS1 activation by reducing its phosphorylation. Mechanistically, LATS1 acetylation resulted in inhibition of YAP phosphorylation and degradation, leading to increased YAP nucleus translocation and promoted target gene expression. Functionally, LATS1-K751Q, the acetylation mimic mutant potentiated lung cancer cell migration, invasion and tumor growth, whereas LATS1-K751R, the acetylation deficient mutant inhibited these functions. Taken together, we demonstrated a previously unidentified post-translational modification of LATS1 that converts LATS1 from a tumor suppressor to a tumor promoter by suppression of Hippo signalling through acetylation of LATS1.
大肿瘤抑制因子 1（LATS1）是控制 Hippo 信号通路激活的关键激酶。LATS1 的翻译后修饰调节其激酶活性。然而，LATS1 稳定性和激活的详细机制仍不清楚。在这里，我们报告 LATS1 可被乙酰转移酶 CBP 在 K751 处乙酰化，并且可被去乙酰化酶 SIRT3 和 SIRT4 去乙酰化。K751 处的乙酰化通过减少 LATS1 的泛素化来稳定 LATS1，并通过降低其磷酸化来抑制 LATS1 的激活。在机制上，LATS1 乙酰化导致 YAP 磷酸化和降解的抑制，导致 YAP 核易位增加，并促进靶基因表达。在功能上，LATS1-K751Q，即乙酰化模拟突变体，增强了肺癌细胞的迁移、侵袭和肿瘤生长，而 LATS1-K751R，即乙酰化缺陷突变体，抑制了这些功能。总之，我们证实了 LATS1 的一种以前未被识别的翻译后修饰，通过 LATS1 的乙酰化抑制 Hippo 信号通路，将 LATS1 从肿瘤抑制因子转化为肿瘤促进因子。
