{"id":1693,"date":"2024-04-15T07:37:38","date_gmt":"2024-04-15T07:37:38","guid":{"rendered":"https:\/\/medicine.nus.edu.sg\/medphc\/?p=1693"},"modified":"2024-12-20T06:27:13","modified_gmt":"2024-12-20T06:27:13","slug":"a-glycolytic-metabolite-bypasses-two-hit-tumor-suppression-by-brca2","status":"publish","type":"post","link":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/a-glycolytic-metabolite-bypasses-two-hit-tumor-suppression-by-brca2\/","title":{"rendered":"A glycolytic metabolite bypasses \u2018\u2018two-hit\u2019\u2019 tumor suppression by BRCA2"},"content":{"rendered":"\r\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone  wp-image-2584\" src=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/04\/20240415-KLR-2-300x169.jpg\" alt=\"\" width=\"950\" height=\"535\" srcset=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/04\/20240415-KLR-2-300x169.jpg 300w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/04\/20240415-KLR-2-1024x576.jpg 1024w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/04\/20240415-KLR-2-768x432.jpg 768w, https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/04\/20240415-KLR-2.jpg 1280w\" sizes=\"auto, (max-width: 950px) 100vw, 950px\" \/><\/p>\r\n<p>&nbsp;<\/p>\r\n<p><span style=\"font-size: 18pt;\"><strong>ABSTRACT<br \/><\/strong><\/span><\/p>\r\n<p>Knudson&#8217;s &#8220;two-hit&#8221; 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&#8217;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 dam\u00ad age in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2&#8217;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&#8217;s two-hit requirement could link glycolysis activation by onco\u00ad genes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.<\/p>\r\n<p>Link to full article: <a href=\"https:\/\/www.cell.com\/action\/showPdf?pii=S0092-8674%2824%2900255-1\">https:\/\/pubmed.ncbi.nlm.nih.gov\/38417710\/<\/a><\/p>\r\n","protected":false},"excerpt":{"rendered":"<p>&nbsp; ABSTRACT Knudson&#8217;s &#8220;two-hit&#8221; 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&#8217;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 [&hellip;]<\/p>\n","protected":false},"author":9345,"featured_media":2584,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"site-sidebar-layout":"default","site-content-layout":"default","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"default","adv-header-id-meta":"","stick-header-meta":"default","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"set","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"categories":[5],"tags":[],"class_list":["post-1693","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-publications"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.4 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>A glycolytic metabolite bypasses \u2018\u2018two-hit\u2019\u2019 tumor suppression by BRCA2 - Pharmacology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/a-glycolytic-metabolite-bypasses-two-hit-tumor-suppression-by-brca2\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"A glycolytic metabolite bypasses \u2018\u2018two-hit\u2019\u2019 tumor suppression by BRCA2 - Pharmacology\" \/>\n<meta property=\"og:description\" content=\"&nbsp; ABSTRACT Knudson&#8217;s &#8220;two-hit&#8221; 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&#8217;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 [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/a-glycolytic-metabolite-bypasses-two-hit-tumor-suppression-by-brca2\/\" \/>\n<meta property=\"og:site_name\" content=\"Pharmacology\" \/>\n<meta property=\"article:published_time\" content=\"2024-04-15T07:37:38+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2024-12-20T06:27:13+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/04\/20240415-KLR-2.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"1280\" \/>\n\t<meta property=\"og:image:height\" content=\"720\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Woon Fei\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Woon Fei\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"2 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/a-glycolytic-metabolite-bypasses-two-hit-tumor-suppression-by-brca2\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/a-glycolytic-metabolite-bypasses-two-hit-tumor-suppression-by-brca2\/\"},\"author\":{\"name\":\"Woon Fei\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/#\/schema\/person\/ea3ccd10ab2f2bba51fd804396287cb0\"},\"headline\":\"A glycolytic metabolite bypasses \u2018\u2018two-hit\u2019\u2019 tumor suppression by BRCA2\",\"datePublished\":\"2024-04-15T07:37:38+00:00\",\"dateModified\":\"2024-12-20T06:27:13+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/a-glycolytic-metabolite-bypasses-two-hit-tumor-suppression-by-brca2\/\"},\"wordCount\":175,\"publisher\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/#organization\"},\"image\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/a-glycolytic-metabolite-bypasses-two-hit-tumor-suppression-by-brca2\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2024\/04\/20240415-KLR-2.jpg\",\"articleSection\":[\"Publications\"],\"inLanguage\":\"en-US\"},{\"@type\":\"WebPage\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/a-glycolytic-metabolite-bypasses-two-hit-tumor-suppression-by-brca2\/\",\"url\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/a-glycolytic-metabolite-bypasses-two-hit-tumor-suppression-by-brca2\/\",\"name\":\"A glycolytic metabolite bypasses \u2018\u2018two-hit\u2019\u2019 tumor suppression by BRCA2 - 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