Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Cancer Data Science Lab (CDSL), National Cancer Institute, National Institute of Health, Bethesda, MD, USA.
Nat Cell Biol. 2022 Sep;24(9):1422-1432. doi: 10.1038/s41556-022-00985-x. Epub 2022 Sep 1.
Tumour dependency on specific metabolic signals has been demonstrated and often guided numerous therapeutic approaches. We identify melanoma addiction to the mitochondrial protein glutaryl-CoA dehydrogenase (GCDH), which functions in lysine metabolism and controls protein glutarylation. GCDH knockdown induced cell death programmes in melanoma cells, an activity blocked by inhibition of the upstream lysine catabolism enzyme DHTKD1. The transcription factor NRF2 mediates GCDH-dependent melanoma cell death programmes. Mechanistically, GCDH knockdown induces NRF2 glutarylation, increasing its stability and DNA binding activity, with a concomitant transcriptional upregulation of ATF4, ATF3, DDIT3 and CHAC1, resulting in cell death. In vivo, inducible inactivation of GCDH effectively inhibited melanoma tumour growth. Correspondingly, reduced GCDH expression correlated with improved survival of patients with melanoma. These findings identify melanoma cell addiction to GCDH, limiting apoptotic signalling by controlling NRF2 glutarylation. Inhibiting the GCDH pathway could thus represent a therapeutic approach to treat melanoma.
肿瘤对特定代谢信号的依赖已得到证实，并常常指导着众多治疗方法。我们发现黑色素瘤依赖于线粒体蛋白谷氨酰辅酶 A 脱氢酶（GCDH），该酶在赖氨酸代谢中发挥作用，并控制蛋白质的戊二酰化。GCDH 敲低诱导黑色素瘤细胞发生细胞死亡程序，而上游赖氨酸分解代谢酶 DHTKD1 的抑制可阻断该活性。转录因子 NRF2 介导 GCDH 依赖性黑色素瘤细胞死亡程序。从机制上讲，GCDH 敲低诱导 NRF2 戊二酰化，增加其稳定性和 DNA 结合活性，同时伴随 ATF4、ATF3、DDIT3 和 CHAC1 的转录上调，导致细胞死亡。在体内，诱导性 GCDH 失活可有效抑制黑色素瘤肿瘤生长。相应地，黑色素瘤患者中 GCDH 表达降低与生存改善相关。这些发现确定了黑色素瘤细胞对 GCDH 的依赖性，通过控制 NRF2 的戊二酰化限制了凋亡信号。因此，抑制 GCDH 途径可能代表治疗黑色素瘤的一种治疗方法。
