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

Zhong Wu; Jin Zhou; Xiaoyang Zhang; Zhouwei Zhang; Yingtian Xie; Jie Bin Liu; Zandra V Ho; Arpit Panda; Xintao Qiu; Paloma Cejas; Israel Cañadas; Fahire Goknur Akarca; James M McFarland; Ankur K Nagaraja; Louisa B Goss; Nikolas Kesten; Longlong Si; Klothilda Lim; Yanli Liu; Yanxi Zhang; Ji Yeon Baek; Yang Liu; Deepa T Patil; Jonathan P Katz; Josephine Hai; Chunyang Bao; Matthew Stachler; Jun Qi; Jeffrey J Ishizuka; Hiroshi Nakagawa; Anil K Rustgi; Kwok-Kin Wong; Matthew Meyerson; David A Barbie; Myles Brown; Henry Long; Adam J Bass

doi:10.1038/s41588-021-00859-2

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

Nat Genet. 2021 Jun;53(6):881-894. doi: 10.1038/s41588-021-00859-2. Epub 2021 May 10.

Authors

Zhong Wu^#^{1

2}, Jin Zhou^#^{1

2}, Xiaoyang Zhang^#^{1

2

3}, Zhouwei Zhang^{1

2}, Yingtian Xie⁴, Jie Bin Liu¹, Zandra V Ho², Arpit Panda^{1

5}, Xintao Qiu⁴, Paloma Cejas⁴, Israel Cañadas^{1

6}, Fahire Goknur Akarca¹, James M McFarland², Ankur K Nagaraja^{1

2

7}, Louisa B Goss¹, Nikolas Kesten^{1

4}, Longlong Si⁸, Klothilda Lim⁴, Yanli Liu³, Yanxi Zhang¹, Ji Yeon Baek¹, Yang Liu^{1

2}, Deepa T Patil⁹, Jonathan P Katz¹⁰, Josephine Hai¹, Chunyang Bao^{1

2}, Matthew Stachler^{1

9}, Jun Qi¹¹, Jeffrey J Ishizuka^{1

2}, Hiroshi Nakagawa¹², Anil K Rustgi¹², Kwok-Kin Wong¹³, Matthew Meyerson^{1

2}, David A Barbie^{1

2}, Myles Brown^{1

4}, Henry Long⁴, Adam J Bass^{14

15

16}

Affiliations

¹ Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
² Cancer Program, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
³ Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
⁴ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁵ Committee on Immunology, The University of Chicago, Chicago, IL, USA.
⁶ Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
⁷ Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
⁸ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
⁹ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹¹ Cancer Biology Department, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
¹² Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA.
¹³ Division of Hematology and Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
¹⁴ Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. ab5147@cumc.columbia.edu.
¹⁵ Cancer Program, The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. ab5147@cumc.columbia.edu.
¹⁶ Herbert Irving Comprehensive Cancer Center, Division of Hematology and Oncology, Department of Medicine, Columbia University, New York, NY, USA. ab5147@cumc.columbia.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions / genetics
Adenosine Deaminase / metabolism*
Animals
Base Sequence
Carcinogenesis / genetics
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Endogenous Retroviruses / genetics
Enhancer Elements, Genetic / genetics
Epigenome*
Esophageal Neoplasms / genetics*
Esophageal Squamous Cell Carcinoma / genetics*
Gene Expression Regulation, Neoplastic
Genome, Human
Humans
Interferons / metabolism
Introns / genetics
Kruppel-Like Transcription Factors / genetics
Mice
Organoids / pathology
Protein Binding
RNA, Double-Stranded / metabolism
RNA-Binding Proteins / metabolism*
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism*
Tumor Suppressor Protein p53 / metabolism

Substances

3' Untranslated Regions
CDKN2A protein, human
Cyclin-Dependent Kinase Inhibitor p16
KLF5 protein, human
Kruppel-Like Transcription Factors
RNA, Double-Stranded
RNA-Binding Proteins
SOX2 protein, human
SOXB1 Transcription Factors
Tumor Suppressor Protein p53
Interferons
ADAR protein, human
Adenosine Deaminase

Abstract

Publication types

MeSH terms

Substances

Grants and funding