Global crotonylome reveals hypoxia-mediated lamin A crotonylation regulated by HDAC6 in liver cancer

  • Cell Death Dis. 2022 Aug 17;13(8):717. doi: 10.1038/s41419-022-05165-1.
Dan Zhang   #  1  2 ,  Jing Tang   #  1  2 ,  Yunhong Xu   #  1  2 ,  Xiaoju Huang  1  2 ,  Yilin Wang  2 ,  Xin Jin  3  4 ,  Gang Wu  5  6 ,  Pian Liu  7  8
Affiliations
  • 1. Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 2. Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 3. Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China. [email protected].
  • 4. Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China. [email protected].
  • 5. Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. [email protected].
  • 6. Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. [email protected].
  • 7. Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. [email protected].
  • 8. Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. [email protected].
  • # Contributed equally.
PMID: 35977926 DOI: 10.1038/s41419-022-05165-1
Abstract

Lysine crotonylation is a recently discovered post-translation modification involved in transcription regulation, cell signal transduction, and Other processes. Scientists have identified several crotonylases and decrotonylases of histones, including P300/CBP, HDACs, and SIRTs. However, the regulation of non-histone protein crotonylation remains unclear. In the current study, we verified that crotonylation was upregulated in hypoxia and promoted liver Cancer cell growth. We performed TMT-labeled quantitative lysine crotonylome analysis in 12 pairs of hepatocellular carcinoma and adjacent liver tissue and identified 3,793 lysine crotonylation sites in 1,428 proteins. We showed that crotonylation of lamin A at the site of K265/270 maintains its subcellular position, promotes liver Cancer cell proliferation, and prevents cellular senescence. Our data indicate that HDAC6 is the decrotonylase of lamin A and downregulated in response to hypoxia, resulting in lamin A K265/270cr. Taken together, our study reveals the lamin A crotonylation in liver Cancer progression and fills the research gap in non-histone protein crotonylation function.

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