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Nat Genet DOI:10.1038/s41588-021-00859-2

Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence.

Publication TypeJournal Article
Year of Publication2021
AuthorsWu, Z, Zhou, J, Zhang, X, Zhang, Z, Xie, Y, Bin Liu, J, Ho, ZV, Panda, A, Qiu, X, Cejas, P, Cañadas, I, Akarca, FGoknur, McFarland, JM, Nagaraja, AK, Goss, LB, Kesten, N, Si, L, Lim, K, Liu, Y, Zhang, Y, Baek, JYeon, Liu, Y, Patil, DT, Katz, JP, Hai, J, Bao, C, Stachler, M, Qi, J, Ishizuka, JJ, Nakagawa, H, Rustgi, AK, Wong, K-K, Meyerson, M, Barbie, DA, Brown, M, Long, H, Bass, AJ
JournalNat Genet
Volume53
Issue6
Pages881-894
Date Published2021 Jun
ISSN1546-1718
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.

DOI10.1038/s41588-021-00859-2
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/33972779?dopt=Abstract

Alternate JournalNat Genet
PubMed ID33972779
Grant ListCA196932 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /
CA187119 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /
CA215244 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /