School of Basic Medical Sciences, Nanchang University, Nanchang, 330031, P. R. China.
School of Life Sciences, Nanchang University, Nanchang, 330031, P.R. China.
Int J Biol Sci. 2022 Jul 4;18(11):4452-4465. doi: 10.7150/ijbs.69882. eCollection 2022.
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, GAC 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.
通过谷氨酰胺酶（GAC）抑制癌症代谢是破坏肿瘤进展的一种有前途的策略。然而，关于 GAC 乙酰化的机制在很大程度上仍然未知。在这项研究中，我们证明赖氨酸乙酰化是一种重要的翻译后修饰，可抑制非小细胞肺癌（NSCLC）中的 GAC 活性。我们确定 GAC 上的赖氨酸 311 是关键的乙酰化位点，该位点被 II 类去乙酰化酶 HDAC4 去乙酰化。赖氨酸 311 的乙酰化刺激 GAC 与三基序（TRIM）家族的 E3 泛素连接酶 TRIM21 之间的相互作用，从而促进 GAC K63 连接的泛素化并抑制 GAC 活性。此外，A549 细胞中的 GAC 突变可降低细胞增殖并减轻肿瘤恶性程度。我们的研究结果揭示了 GAC 通过乙酰化和泛素化调节参与非小细胞肺癌发生的新机制。
