美国普雷比斯医学研究所Ze’ev A. Ronai团队发现，NRF2通过调控凋亡信号介导黑色素瘤对GCDH的依赖。相关论文于2022年9月1日发表在《自然—细胞生物学》杂志上。

研究人员发现黑色素瘤对线粒体蛋白戊二酰辅酶A脱氢酶 (GCDH) 存在依赖性，该酶在赖氨酸代谢中起作用并控制蛋白质戊二酰化。GCDH敲低可激活黑色素瘤细胞的细胞死亡程序，这种活性可通过抑制上游赖氨酸分解代谢酶DHTKD1所阻断。转录因子NRF2介导GCDH依赖的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，并伴随ATF4、ATF3、DDIT3和CHAC1的转录上调，导致细胞死亡。在体内，GCDH的失活有效地抑制了黑色素瘤的生长。相应地，降低GCDH的表达与改善黑色素瘤患者的生存率相关。这些发现确定了黑色素瘤细胞对GCDH的依赖性，其通过控制NRF2戊二酰化来抑制凋亡信号。因此，抑制GCDH途径可作为黑色素瘤的治疗方法之一。

研究人员表示，肿瘤对特定代谢信号的依赖性已被证明并作为许多治疗方法的靶点。

附：英文原文

Title: NRF2 mediates melanoma addiction to GCDH by modulating apoptotic signalling

Author: Verma, Sachin, Crawford, David, Khateb, Ali, Feng, Yongmei, Sergienko, Eduard, Pathria, Gaurav, Ma, Chen-Ting, Olson, Steven H., Scott, David, Murad, Rabi, Ruppin, Eytan, Jackson, Michael, Ronai, Zeev A.

Issue&Volume: 2022-09-01

Abstract: 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.

DOI: 10.1038/s41556-022-00985-x

Source: https://www.nature.com/articles/s41556-022-00985-x