{"id":122992,"date":"2021-05-25T02:12:16","date_gmt":"2021-05-25T09:12:16","guid":{"rendered":"https:\/\/lifeboat.com\/blog\/2021\/05\/genome-scale-crispr-cas9-screen-of-wnt-%ce%b2-catenin-signaling-identifies-therapeutic-targets-for-colorectal-cancer"},"modified":"2021-05-25T02:12:16","modified_gmt":"2021-05-25T09:12:16","slug":"genome-scale-crispr-cas9-screen-of-wnt-%ce%b2-catenin-signaling-identifies-therapeutic-targets-for-colorectal-cancer","status":"publish","type":"post","link":"https:\/\/lifeboat.com\/blog\/2021\/05\/genome-scale-crispr-cas9-screen-of-wnt-%ce%b2-catenin-signaling-identifies-therapeutic-targets-for-colorectal-cancer","title":{"rendered":"Genome-scale CRISPR-Cas9 screen of Wnt\/\u03b2-catenin signaling identifies therapeutic targets for colorectal cancer"},"content":{"rendered":"

<\/a><\/p>\n

Aberrant activation of Wnt\/\u03b2-catenin pathway is a key driver of colorectal cancer (CRC) growth and of great therapeutic importance. In this study, we performed comprehensive CRISPR screens to interrogate the regulatory network of Wnt\/\u03b2-catenin signaling in CRC cells. We found marked discrepancies between the artificial TOP reporter activity and \u03b2-catenin\u2013mediated endogenous transcription and redundant roles of T cell factor\/lymphoid enhancer factor transcription factors in transducing \u03b2-catenin signaling. Compiled functional genomic screens and network analysis revealed unique epigenetic regulators of \u03b2-catenin transcriptional output, including the histone lysine methyltransferase 2A oncoprotein (KMT2A\/Mll1). Using an integrative epigenomic and transcriptional profiling approach, we show that KMT2A loss diminishes the binding of \u03b2-catenin to consensus DNA motifs and the transcription of \u03b2-catenin targets in CRC. These results suggest that KMT2A may be a promising target for CRCs and highlight the broader potential for exploiting epigenetic modulation as a therapeutic strategy for \u03b2-catenin\u2013driven malignancies.<\/p>\n

Colorectal cancer (CRC) represents one of the major malignancies and a leading cause of cancer-related death worldwide. Aberrant Wnt\/\u03b2-catenin pathway plays a pivotal role in colon carcinogenesis (1<\/em><\/a>). Cytoplasmic \u03b2-catenin is phosphorylated by a protein complex containing adenomatous polyposis coli (APC), AXIN1 or AXIN2, casein kinase 1\u03b1 (CK1\u03b1), and glycogen synthase kinase-3\u03b2 (GSK3\u03b2), leading to \u03b2-catenin destruction through ubiquitin-proteasome system. Wnt binding to the LDL receptor related protein 5\/6 (LRP5\/6)\u2013frizzled receptors results in the disassembly of the \u03b2-catenin\u2013destruction complex and consequent accumulation of \u03b2-catenin. \u03b2-Catenin then enters into the nucleus and binds to T cell factor\/lymphoid enhancer factor (TCF\/LEF) transcription factors to initiate the transcription of \u03b2-catenin downstream targets (2<\/em><\/a>).<\/p>\n

Nearly all colorectal tumors (CRC) harbor genetic mutations that lead to the hyperactivation of \u03b2-catenin signaling. For example, germline or spontaneous mutations in tumor suppressor APC may cause constitutive activation of \u03b2-catenin in colon stem cells and the development of colonic polyps, which may eventually evolve into colorectal carcinomas. Hyperactivated \u03b2-catenin initiates the expression of various downstream targets through binding to the promoter regions via TCF\/LEF transcription factors. Studies using transcriptomic approaches have characterized various \u03b2-catenin\u2013responsive targets, such as cMYC, AXIN2, ASCL2, LGR5, and CD44. Collectively, these targets promote proliferation (e.g., cMYC) and maintain a stem cell state (e.g., LGR5 and ASCL2), highlighting the potential value of developing treatments that target \u03b2-catenin signaling in cancer. However, \u03b2-catenin itself is an intractable drug target (6, 7).<\/p>\n","protected":false},"excerpt":{"rendered":"

Aberrant activation of Wnt\/\u03b2-catenin pathway is a key driver of colorectal cancer (CRC) growth and of great therapeutic importance. In this study, we performed comprehensive CRISPR screens to interrogate the regulatory network of Wnt\/\u03b2-catenin signaling in CRC cells. We found marked discrepancies between the artificial TOP reporter activity and \u03b2-catenin\u2013mediated endogenous transcription and redundant roles [\u2026]<\/p>\n","protected":false},"author":630,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[11,412],"tags":[],"class_list":["post-122992","post","type-post","status-publish","format-standard","hentry","category-biotech-medical","category-genetics"],"_links":{"self":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/122992","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/users\/630"}],"replies":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/comments?post=122992"}],"version-history":[{"count":0,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/122992\/revisions"}],"wp:attachment":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/media?parent=122992"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/categories?post=122992"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/tags?post=122992"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}