Department of Medical Genetics, Peking University Health Science Center, Beijing, China.
Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark.
Cancer Res. 2018 Jan 15;78(2):372-386. doi: 10.1158/0008-5472.CAN-17-1912. Epub 2017 Nov 27.
The mitochondrial serine hydroxymethyltransferase SHMT2, which catalyzes the rate-limiting step in serine catabolism, drives cancer cell proliferation, but how this role is regulated is undefined. Here, we report that the sirtuin SIRT5 desuccinylates SHMT2 to increase its activity and drive serine catabolism in tumor cells. SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2, which was crucial for activating its enzymatic activity. Conversely, hypersuccinylation of SHMT2 at lysine 280 was sufficient to inhibit its enzymatic activity and downregulate tumor cell growth and Notably, SIRT5 inactivation led to SHMT2 enzymatic downregulation and to abrogated cell growth under metabolic stress. Our results reveal that SHMT2 desuccinylation is a pivotal signal in cancer cells to adapt serine metabolic processes for rapid growth, and they highlight SIRT5 as a candidate target for suppressing serine catabolism as a strategy to block tumor growth. These findings reveal a novel mechanism for controlling cancer cell proliferation by blocking serine catabolism, as a general strategy to impede tumor growth. .
线粒体丝氨酸羟甲基转移酶 2（SHMT2）催化丝氨酸分解代谢的限速步骤，驱动癌细胞增殖，但这种作用如何被调节尚不清楚。在这里，我们报告说，去琥珀酰化酶 SIRT5 去琥珀酰化 SHMT2，以增加其活性并促进肿瘤细胞中的丝氨酸分解代谢。SIRT5 相互作用直接介导 SHMT2 赖氨酸 280 上的去琥珀酰化，这对于激活其酶活性至关重要。相反，赖氨酸 280 上的 SHMT2 过度琥珀酰化足以抑制其酶活性并下调肿瘤细胞生长。值得注意的是，SIRT5 失活导致 SHMT2 酶下调，并在代谢应激下阻断细胞生长。我们的结果表明，SHMT2 去琥珀酰化是癌细胞适应丝氨酸代谢过程以快速生长的关键信号，并且它们突出了 SIRT5 作为抑制丝氨酸分解代谢作为阻断肿瘤生长策略的候选靶点。这些发现揭示了通过阻断丝氨酸分解代谢来控制癌细胞增殖的新机制，这是一种阻止肿瘤生长的通用策略。
