近日，新加坡国立大学Ashok R. Venkitaraman及其课题组发现，一种糖酵解代谢物通过BRCA2可绕过对肿瘤的“二次打击”抑制作用。2024年4月11日，《细胞》杂志在线发表了这项成果。
研究人员报告了糖酵解代谢物丙酮醛（MGO）通过使乳腺癌抑制蛋白BRCA2失活，在非恶性乳腺细胞或患者衍生的器官组织中诱发癌症相关的突变单碱基置换（SBS）特征，从而瞬时绕过Knudson的范式。种系单等位基因BRCA2突变易导致这些变化。在Kras驱动、Brca2突变的小鼠胰腺癌和人类乳腺癌中，MGO积累和DNA损伤伴随着类似的SBS特征，但同样没有双侧BRCA2失活。
MGO会引发BRCA2蛋白分解，使BRCA2在DNA修复和复制中的肿瘤抑制功能暂时失效，从而导致功能性单倍体缺陷。间歇性接触MGO会诱发偶发性SBS突变，但不会导致BRCA2永久失活。因此，MGO诱导的BRCA2单倍性不足可暂时绕过Knudson的二次打击要求，这种代谢机制可将癌基因、代谢紊乱或饮食挑战激活的糖酵解与癌症演化中的突变特征联系起来。
研究人员表示，Knudson的“二次打击”范式认为，致癌需要常染色体肿瘤抑制基因的两个拷贝都失活。
附：英文原文
Title: A glycolytic metabolite bypasses “two-hit” tumor suppression by BRCA2
Author: Li Ren Kong, Komal Gupta, Andy Jialun Wu, David Perera, Roland Ivanyi-Nagy, Syed Moiz Ahmed, Tuan Zea Tan, Shawn Lu-Wen Tan, Alessandra Fuddin, Elayanambi Sundaramoorthy, Grace Shiqing Goh, Regina Tong Xin Wong, Ana S.H. Costa, Callum Oddy, Hannan Wong, C. Pawan K. Patro, Yun Suen Kho, Xiao Zi Huang, Joan Choo, Mona Shehata, Soo Chin Lee, Boon Cher Goh, Christian Frezza, Jason J. Pitt, Ashok R. Venkitaraman
Issue&Volume: 2024-04-11
Abstract: Knudson’s “two-hit” paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson’s paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2’s tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson’s two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.
DOI: 10.1016/j.cell.2024.03.006
Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00255-1