Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Cell Death Dis. 2022 Aug 17;13(8):717. doi: 10.1038/s41419-022-05165-1.
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.
赖氨酸巴豆酰化是一种新发现的参与转录调控、细胞信号转导等过程的翻译后修饰。科学家已经鉴定了几种组蛋白的巴豆酰基转移酶和脱巴豆酰基酶，包括 P300/CBP、HDACs 和 SIRTs。然而，非组蛋白蛋白巴豆酰化的调节尚不清楚。在本研究中，我们验证了缺氧可上调巴豆酰化并促进肝癌细胞生长。我们在 12 对肝癌及其相邻肝组织中进行了 TMT 标记的定量赖氨酸巴豆酰化组学分析，在 1428 种蛋白质中鉴定出 3793 个赖氨酸巴豆酰化位点。我们表明，核纤层蛋白 A 在 K265/270 位点的巴豆酰化维持其亚细胞位置，促进肝癌细胞增殖，并防止细胞衰老。我们的数据表明，HDAC6 是核纤层蛋白 A 的脱巴豆酰基酶，并且对缺氧有反应性地下调，导致核纤层蛋白 A K265/270cr。总之，我们的研究揭示了肝癌进展中的核纤层蛋白 A 巴豆酰化，并填补了非组蛋白蛋白巴豆酰化功能研究的空白。
