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

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 ZhangJi 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

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

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.

Original language	English
Pages (from-to)	881-894
Number of pages	14
Journal	Nature Genetics
Volume	53
Issue number	6
DOIs	https://doi.org/10.1038/s41588-021-00859-2
State	Published - May 2021

Keywords

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
Tumor Suppressor Protein p53/metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41588-021-00859-2

Cite this

Wu, Z., Zhou, J., Zhang, X., Zhang, Z., Xie, Y., Liu, J. B., Ho, Z. V., Panda, A., Qiu, X., Cejas, P., Cañadas, I., Akarca, F. G., McFarland, J. M., Nagaraja, A. K., Goss, L. B., Kesten, N., Si, L., Lim, K., Liu, Y., ... Bass, A. J. (2021). Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence. Nature Genetics, 53(6), 881-894. https://doi.org/10.1038/s41588-021-00859-2

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title = "Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence",

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.",

keywords = "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, Tumor Suppressor Protein p53/metabolism",

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

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = may,

doi = "10.1038/s41588-021-00859-2",

language = "English",

volume = "53",

pages = "881--894",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "6",

}

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 2021, 'Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence', Nature Genetics, vol. 53, no. 6, pp. 881-894. https://doi.org/10.1038/s41588-021-00859-2

TY - JOUR

T1 - Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence

AU - Wu, Zhong

AU - Zhou, Jin

AU - Zhang, Xiaoyang

AU - Zhang, Zhouwei

AU - Xie, Yingtian

AU - Liu, Jie bin

AU - Ho, Zandra V.

AU - Panda, Arpit

AU - Qiu, Xintao

AU - Cejas, Paloma

AU - Cañadas, Israel

AU - Akarca, Fahire Goknur

AU - McFarland, James M.

AU - Nagaraja, Ankur K.

AU - Goss, Louisa B.

AU - Kesten, Nikolas

AU - Si, Longlong

AU - Lim, Klothilda

AU - Liu, Yanli

AU - Zhang, Yanxi

AU - Baek, Ji Yeon

AU - Liu, Yang

AU - Patil, Deepa T.

AU - Katz, Jonathan P.

AU - Hai, Josephine

AU - Bao, Chunyang

AU - Stachler, Matthew

AU - Qi, Jun

AU - Ishizuka, Jeffrey J.

AU - Nakagawa, Hiroshi

AU - Rustgi, Anil K.

AU - Wong, Kwok Kin

AU - Meyerson, Matthew

AU - Barbie, David A.

AU - Brown, Myles

AU - Long, Henry

AU - Bass, Adam J.

PY - 2021/5

Y1 - 2021/5

N2 - 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.

AB - 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.

KW - 3' Untranslated Regions/genetics

KW - Adenosine Deaminase/metabolism

KW - Animals

KW - Base Sequence

KW - Carcinogenesis/genetics

KW - Cell Line, Tumor

KW - Cell Transformation, Neoplastic/genetics

KW - Cyclin-Dependent Kinase Inhibitor p16/metabolism

KW - Endogenous Retroviruses/genetics

KW - Enhancer Elements, Genetic/genetics

KW - Epigenome

KW - Esophageal Neoplasms/genetics

KW - Esophageal Squamous Cell Carcinoma/genetics

KW - Gene Expression Regulation, Neoplastic

KW - Genome, Human

KW - Humans

KW - Interferons/metabolism

KW - Introns/genetics

KW - Kruppel-Like Transcription Factors/genetics

KW - Mice

KW - Organoids/pathology

KW - Protein Binding

KW - RNA, Double-Stranded/metabolism

KW - RNA-Binding Proteins/metabolism

KW - SOXB1 Transcription Factors/genetics

KW - Tumor Suppressor Protein p53/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85105939962&partnerID=8YFLogxK

U2 - 10.1038/s41588-021-00859-2

DO - 10.1038/s41588-021-00859-2

M3 - Article

C2 - 33972779

AN - SCOPUS:85105939962

SN - 1061-4036

VL - 53

SP - 881

EP - 894

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

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