Int J Biol Sci 2022; 18(11):4452-4465. doi:10.7150/ijbs.69882 This issue

Research Paper

Deacetylation of Glutaminase by HDAC4 contributes to Lung Cancer Tumorigenesis

Tao Wang1, Zhuo Lu2, Tianyu Han3, Yanan Wang2, Mingxi Gan1, Jian-Bin Wang1✉

1. School of Basic Medical Sciences, Nanchang University, Nanchang, 330031, P. R. China.
2. School of Life Sciences, Nanchang University, Nanchang, 330031, P.R. China.
3. Jiangxi Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, P.R. China.

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Citation:
Wang T, Lu Z, Han T, Wang Y, Gan M, Wang JB. Deacetylation of Glutaminase by HDAC4 contributes to Lung Cancer Tumorigenesis. Int J Biol Sci 2022; 18(11):4452-4465. doi:10.7150/ijbs.69882. Available from https://www.ijbs.com/v18p4452.htm

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Abstract

Graphic abstract

Inhibiting cancer metabolism via glutaminase (GAC) is a promising strategy to disrupt tumor progression. However, mechanism regarding GAC acetylation remains mostly unknown. In this study, we demonstrate that lysine acetylation is a vital post-translational modification that inhibits GAC activity in non-small cell lung cancer (NSCLC). We identify that Lys311 is the key acetylation site on GAC, which is deacetylated by HDAC4, a class II deacetylase. Lys311 acetylation stimulates the interaction between GAC and TRIM21, an E3 ubiquitin ligase of the tripartite motif (TRIM) family, therefore promoting GAC K63-linked ubiquitination and inhibiting GAC activity. Furthermore, GACK311Q mutation in A549 cells decreases cell proliferation and alleviates tumor malignancy. Our findings reveal a novel mechanism of GAC regulation by acetylation and ubiquitination that participates in non-small cell lung cancer tumorigenesis.

Keywords: glutaminase, acetylation, HDAC4, TRIM21, non-small cell lung cancer