Author:
Zhang Xin-yue,Liu Ze-xian,Zhang Yi-fan,Xu Li-xia,Chen Meng-ke,Zhou Yu-feng,Yu Jun,Li Xiao-xing,Zhang Ning
Abstract
Abstract
Background
Hepatocellular carcinoma (HCC) metastasis and recurrence lead to therapy failure, which are closely associated with the proteome. However, the role of post-translational modification (PTM) in HCC, especially for the recently discovered lysine crotonylation (Kcr), is elusive.
Results
We investigated the correlation between crotonylation and HCC in 100 tumor tissues and performed stable isotope labeling by amino acids and liquid chromatography tandem mass spectrometry in HCC cells, and we found that crotonylation was positively correlated with HCC metastasis, and higher crotonylation in HCC cells facilitated cell invasiveness. Through bioinformatic analysis, we found that the crotonylated protein SEPT2 was significantly hypercrotonylated in highly invasive cells, while the decrotonylated mutation of SEPT2-K74 impaired SEPT2 GTPase activity and inhibited HCC metastasis in vitro and in vivo. Mechanistically, SIRT2 decrotonylated SEPT2, and P85α was found to be the downstream effector of SEPT2. Moreover, we identified that SEPT2-K74cr was correlated with poor prognosis and recurrence in HCC patients, thus indicating its clinical potential as an independent prognostic factor.
Conclusions
We revealed the role of nonhistone protein crotonylation in regulating HCC metastasis and invasion. Crotonylation facilitated cell invasion through the crotonylated SEPT2-K74-P85α-AKT pathway. High SEPT2-K74 crotonylation predicted poor prognosis and a high recurrence rate in HCC patients. Our study revealed a novel role of crotonylation in promoting HCC metastasis.
Funder
The project was supported by National Key R&D Program of China
Natural Science Foundation of China
the Nature Science Foundation of Guangdong
Program for Guangdong Introducing Innovative and Entrepreneurial Teams
Tip-top Scientific and Technical Innovative Youth Talents of Guangdong Special Support Program
Publisher
Springer Science and Business Media LLC
Subject
General Biochemistry, Genetics and Molecular Biology
Cited by
7 articles.
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