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Wu Z , Zhou J , Zhang X , Zhang Z , Xie Y , Liu JB , Ho ZV , Panda A , Qiu X , Cejas P , Cañadas I , Akarca FG , McFarland JM , Nagaraja AK , Goss LB , Kesten N , Si L , Lim K , Liu Y , Zhang Y , Baek JY , Liu Y , Patil DT , Katz JP , Hai J , Bao C , Stachler M , Qi J , Ishizuka JJ , Nakagawa H , Rustgi AK , Wong KK , Meyerson M , Barbie DA , Brown M , Long H , Bass AJ
Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence
Nat Genet. 2021 May 10
PMID: 33972779   
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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.
Notes
1546-1718 Wu, Zhong Zhou, Jin Zhang, Xiaoyang Orcid: 0000-0002-0031-0290 Zhang, Zhouwei Xie, Yingtian Liu, Jie Bin Ho, Zandra V Orcid: 0000-0003-4046-0266 Panda, Arpit Qiu, Xintao Orcid: 0000-0002-8560-7017 Cejas, Paloma Cañadas, Israel Akarca, Fahire Goknur Orcid: 0000-0003-2254-3279 McFarland, James M Orcid: 0000-0001-9978-480x Nagaraja, Ankur K Orcid: 0000-0002-8586-3117 Goss, Louisa B Kesten, Nikolas Si, Longlong Lim, Klothilda Liu, Yanli Zhang, Yanxi Baek, Ji Yeon Liu, Yang Patil, Deepa T Katz, Jonathan P Orcid: 0000-0001-6922-1707 Hai, Josephine Bao, Chunyang Orcid: 0000-0001-7962-346x Stachler, Matthew Qi, Jun Orcid: 0000-0002-1461-3356 Ishizuka, Jeffrey J Nakagawa, Hiroshi Rustgi, Anil K Wong, Kwok-Kin Orcid: 0000-0001-6323-235x Meyerson, Matthew Barbie, David A Brown, Myles Long, Henry Orcid: 0000-0001-6849-6629 Bass, Adam J Orcid: 0000-0002-8193-4758 CA196932/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)/ Journal Article United States Nat Genet. 2021 May 10. doi: 10.1038/s41588-021-00859-2.