一种糖酵解代谢产物绕过BRCA2的“二击”肿瘤抑制机制

一种糖酵解代谢产物绕过BRCA2的“二击”肿瘤抑制机制

A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2

作者: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

期刊:CELL

摘要

Knudson的“二击”范式提出，癌变需要两份常染色体肿瘤抑制基因的失活。在此，我们报道，糖酵解代谢产物甲基乙二醛（MGO）暂时绕过了Knudson的范式，通过失活乳腺癌抑制蛋白BRCA2，在非恶性乳腺细胞或患者来源的类器官中引发与癌症相关的单碱基突变（SBS）特征。胚系单等位基因BRCA2突变会增加这些变化的易感性。类似的SBS特征，在未发生双等位基因失活的情况下，在Kras驱动的Brca2突变鼠类胰腺癌和人类乳腺癌中伴随MGO积累和DNA损伤出现。MGO促使BRCA2蛋白降解，暂时性失活BRCA2在DNA修复和复制中的肿瘤抑制功能，造成功能性单倍体缺失。间歇性暴露于MGO会引发周期性的SBS突变，而不会导致BRCA2的永久失活。因此，一种代谢机制，即MGO诱导的BRCA2单倍体缺失暂时规避了Knudson的二击需求，可能将肿瘤基因激活引起的糖酵解、代谢紊乱或饮食挑战与癌症演化中的突变特征联系起来。

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.

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