| Literature DB >> 33972779 |
Zhong Wu1,2, Jin Zhou1,2, Xiaoyang Zhang1,2,3, Zhouwei Zhang1,2, Yingtian Xie4, Jie Bin Liu1, Zandra V Ho2, Arpit Panda1,5, Xintao Qiu4, Paloma Cejas4, Israel Cañadas1,6, Fahire Goknur Akarca1, James M McFarland2, Ankur K Nagaraja1,2,7, Louisa B Goss1, Nikolas Kesten1,4, Longlong Si8, Klothilda Lim4, Yanli Liu3, Yanxi Zhang1, Ji Yeon Baek1, Yang Liu1,2, Deepa T Patil9, Jonathan P Katz10, Josephine Hai1, Chunyang Bao1,2, Matthew Stachler1,9, Jun Qi11, Jeffrey J Ishizuka1,2, Hiroshi Nakagawa12, Anil K Rustgi12, Kwok-Kin Wong13, Matthew Meyerson1,2, David A Barbie1,2, Myles Brown1,4, Henry Long4, Adam J Bass14,15,16.
Abstract
Esophageal squamous cell carcinomas (ESCCs) harbor recurrent chromosome 3q amplifications that target the transcription factor SOX2. Beyond its role as an oncogene in ESCC, SOX2 acts in development of the squamous esophagus and maintenance of adult esophageal precursor cells. To compare Sox2 activity in normal and malignant tissue, we developed engineered murine esophageal organoids spanning normal esophagus to Sox2-induced squamous cell carcinoma and mapped Sox2 binding and the epigenetic and transcriptional landscape with evolution from normal to cancer. While oncogenic Sox2 largely maintains actions observed in normal tissue, Sox2 overexpression with p53 and p16 inactivation promotes chromatin remodeling and evolution of the Sox2 cistrome. With Klf5, oncogenic Sox2 acquires new binding sites and enhances activity of oncogenes such as Stat3. Moreover, oncogenic Sox2 activates endogenous retroviruses, inducing expression of double-stranded RNA and dependence on the RNA editing enzyme ADAR1. These data reveal SOX2 functions in ESCC, defining targetable vulnerabilities.Entities:
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Year: 2021 PMID： 33972779 PMCID： PMC9124436 DOI： 10.1038/s41588-021-00859-2
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 41.307