2. Academic Validation
  3. Inhibition of 14-3-3ε by K50 acetylation activates YAP1 to promote cholangiocarcinoma growth

Inhibition of 14-3-3ε by K50 acetylation activates YAP1 to promote cholangiocarcinoma growth

  • Exp Cell Res. 2022 Dec 15;421(2):113404. doi: 10.1016/j.yexcr.2022.113404.
Kun Fan 1,  Kaihua Zhu 2,  Jiwen Wang 3,  Xiaojian Ni 3,  Sheng Shen 3,  Zijun Gong 3,  Xi Cheng 3,  Cheng Zhang 3,  Han Liu 3,  Tao Suo 4,  Xiaoling Ni 5,  Houbao Liu 6
Affiliations

Affiliations

  • 1 Department of General Surgery, Central Hospital of Xuhui District, China; Department of General Surgery, Zhongshan Hospital, Fudan University, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, China; Cancer Center, Zhongshan Hospital, Fudan University, China; Biliary Tract Disease Institute, Fudan University, China.
  • 2 Department of General Surgery, Central Hospital of Xuhui District, China.
  • 3 Department of General Surgery, Zhongshan Hospital, Fudan University, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, China; Cancer Center, Zhongshan Hospital, Fudan University, China; Biliary Tract Disease Institute, Fudan University, China.
  • 4 Department of General Surgery, Zhongshan Hospital, Fudan University, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, China; Cancer Center, Zhongshan Hospital, Fudan University, China; Biliary Tract Disease Institute, Fudan University, China. Electronic address: [email protected].
  • 5 Department of General Surgery, Zhongshan Hospital, Fudan University, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, China; Cancer Center, Zhongshan Hospital, Fudan University, China; Biliary Tract Disease Institute, Fudan University, China. Electronic address: [email protected].
  • 6 Department of General Surgery, Central Hospital of Xuhui District, China; Department of General Surgery, Zhongshan Hospital, Fudan University, China; Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, China; Cancer Center, Zhongshan Hospital, Fudan University, China; Biliary Tract Disease Institute, Fudan University, China. Electronic address: [email protected].
PMID: 36341908 DOI: 10.1016/j.yexcr.2022.113404
Abstract

14-3-3 proteins are ubiquitous adapters combining with phosphorylated serine/threonine motifs to regulate multiple cellular processes. As a negative regulator, 14-3-3 proteins could sequester the phosphorylated YAP1 in cytoplasm to inhibit its activity. In this study, we identified the K50 acetylation (K50ac) of 14-3-3ε protein and investigated its roles and mechanism in cholangiocarcinoma progression. The NAD (+)-dependent protein deacetylases inhibitor, NAM treatment significantly up-regulated the K50ac of 14-3-3ε. K50R mutation resulted in the decrease of K50ac of 14-3-3ε. The K50ac of 14-3-3ε was reversibly mediated by PCAF acetyltransferase and SIRT1 deacetylases. K50ac had no obvious effect on the protein stability of 14-3-3ε, but inhibited the combination of 14-3-3ε with phosphorylated YAP1, which resulted in the activation of YAP1 in cholangiocarcinoma. K50R significantly decreased cholangiocarcinoma cell proliferation in vitro and the growth of tumor xenograft in vivo compared with WT (wild type) 14-3-3ε. The level of K50ac were higher in cholangiocarcinoma tissues accompanied by the accumulation of YAP1 in nuclear than para-carcinoma tissues. Our study revealed the underlying mechanism of K50ac of 14-3-3ε and its roles in cholangiocarcinoma, providing a potential targeting for cholangiocarcinoma therapy.

Keywords

14-3-3ε; Cholangiocarcinoma; K50 acetylation; YAP1.

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