Wnt信号通路
癌症研究
生物
DNA修复
范科尼贫血
FANCD2
PARP抑制剂
癌症
癌症干细胞
DNA损伤
奥拉帕尼
干细胞
细胞生物学
遗传学
信号转导
基因
DNA
聚ADP核糖聚合酶
聚合酶
作者
Navneet Kaur,Sugunavathi Sepramaniam,Jun Hyung Lim,Siddhi Patnaik,Nathan Harmston,May Ann Lee,Enrico Petretto,David M. Virshup,Babita Madan
标识
DOI:10.1101/2020.06.17.157024
摘要
ABSTRACT Wnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have proven effective in Wnt-addicted preclinical cancer models and are in clinical trials. In a survey for potential combination therapies, we found that Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt-addicted cancers. Mechanistically, we find that multiple genes in the homologous recombination and Fanconi anemia repair pathways, including BRCA1 , FANCD2 , and RAD51 are dependent on Wnt/β-catenin signaling in Wnt-high cancers, and treatment with a PORCN inhibitor creates a BRCA-like state. This coherent regulation of DNA repair genes occurs via a Wnt/β-catenin/MYBL2 axis. Importantly, this pathway also functions in intestinal crypts, where high expression of BRCA and Fanconi anemia genes is seen in intestinal stem cells, with further upregulation in Wnt high APC min mutant polyps. Our findings suggest a general paradigm that Wnt/β-catenin signaling enhances DNA repair in stem cells and cancers to maintain genomic integrity. Conversely, interventions that block Wnt signaling may sensitize cancers to radiation and other DNA damaging agents.
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