Lineage-specific epigenomic and genomic activation of oncogene HNF4A promotes gastrointestinal adenocarcinomas

Jian Pan; Tiago C. Silva; Nicole Gull; Qian Yang; Jasmine T. Plummer; Stephanie Chen; Kenji Daigo; Takao Hamakubo; Sigal Gery; Ling Wen Ding; Yan Yi Jiang; Shaoyan Hu; Li Yan Xu; En Min Li; Yanbing Ding; Samuel J. Klempner; Simon A. Gayther; Benjamin P. Berman; H. Phillip Koeffler; De Chen Lin

doi:10.1158/0008-5472.CAN-20-0390

Lineage-specific epigenomic and genomic activation of oncogene HNF4A promotes gastrointestinal adenocarcinomas

Jian Pan, Tiago C. Silva, Nicole Gull, Qian Yang, Jasmine T. Plummer, Stephanie Chen, Kenji Daigo, Takao Hamakubo, Sigal Gery, Ling Wen Ding, Yan Yi Jiang, Shaoyan Hu, Li Yan Xu, En Min Li, Yanbing Ding, Samuel J. Klempner, Simon A. Gayther, Benjamin P. Berman^*, H. Phillip Koeffler, De Chen Lin^*

^*Corresponding author for this work

Department of Developmental Biology and Cancer Research

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

37 Scopus citations

Abstract

Gastrointestinal adenocarcinomas (GIAC) of the tubular gastrointestinal (GI) tract including esophagus, stomach, colon, and rectum comprise most GI cancers and share a spectrum of genomic features. However, the unified epigenomic changes specific to GIAC are poorly characterized. Using 907 GIAC samples from The Cancer Genome Atlas, we applied mathematical algorithms to large-scale DNA methylome and transcriptome profiles to reconstruct transcription factor (TF) networks and identify a list of functionally hyperactive master regulator (MR) TF shared across different GIAC. The top candidate HNF4A exhibited prominent genomic and epigenomic activation in a GIAC-specific manner. A complex interplay between the HNF4A promoter and three distal enhancer elements was coordinated by GIAC-specific MRTF including ELF3, GATA4, GATA6, and KLF5. HNF4A also self-regulated its own promoter and enhancers. Functionally, HNF4A promoted cancer proliferation and survival by transcriptional activation of many downstream targets, including HNF1A and factors of interleukin signaling, in a lineage-specific manner. Overall, our study provides new insights into the GIAC-specific gene regulatory networks and identifies potential therapeutic strategies against these common cancers.

Original language	English
Pages (from-to)	2722-2736
Number of pages	15
Journal	Cancer Research
Volume	80
Issue number	13
DOIs	https://doi.org/10.1158/0008-5472.CAN-20-0390
State	Published - 1 Jul 2020

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Publisher Copyright:
© 2020 American Association for Cancer Research.

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Pan, J., Silva, T. C., Gull, N., Yang, Q., Plummer, J. T., Chen, S., Daigo, K., Hamakubo, T., Gery, S., Ding, L. W., Jiang, Y. Y., Hu, S., Xu, L. Y., Li, E. M., Ding, Y., Klempner, S. J., Gayther, S. A., Berman, B. P., Phillip Koeffler, H., & Lin, D. C. (2020). Lineage-specific epigenomic and genomic activation of oncogene HNF4A promotes gastrointestinal adenocarcinomas. Cancer Research, 80(13), 2722-2736. https://doi.org/10.1158/0008-5472.CAN-20-0390

@article{8412cd29af3f40808af8ac48840a8da2,

title = "Lineage-specific epigenomic and genomic activation of oncogene HNF4A promotes gastrointestinal adenocarcinomas",

abstract = "Gastrointestinal adenocarcinomas (GIAC) of the tubular gastrointestinal (GI) tract including esophagus, stomach, colon, and rectum comprise most GI cancers and share a spectrum of genomic features. However, the unified epigenomic changes specific to GIAC are poorly characterized. Using 907 GIAC samples from The Cancer Genome Atlas, we applied mathematical algorithms to large-scale DNA methylome and transcriptome profiles to reconstruct transcription factor (TF) networks and identify a list of functionally hyperactive master regulator (MR) TF shared across different GIAC. The top candidate HNF4A exhibited prominent genomic and epigenomic activation in a GIAC-specific manner. A complex interplay between the HNF4A promoter and three distal enhancer elements was coordinated by GIAC-specific MRTF including ELF3, GATA4, GATA6, and KLF5. HNF4A also self-regulated its own promoter and enhancers. Functionally, HNF4A promoted cancer proliferation and survival by transcriptional activation of many downstream targets, including HNF1A and factors of interleukin signaling, in a lineage-specific manner. Overall, our study provides new insights into the GIAC-specific gene regulatory networks and identifies potential therapeutic strategies against these common cancers.",

author = "Jian Pan and Silva, {Tiago C.} and Nicole Gull and Qian Yang and Plummer, {Jasmine T.} and Stephanie Chen and Kenji Daigo and Takao Hamakubo and Sigal Gery and Ding, {Ling Wen} and Jiang, {Yan Yi} and Shaoyan Hu and Xu, {Li Yan} and Li, {En Min} and Yanbing Ding and Klempner, {Samuel J.} and Gayther, {Simon A.} and Berman, {Benjamin P.} and {Phillip Koeffler}, H. and Lin, {De Chen}",

note = "Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2020",

month = jul,

day = "1",

doi = "10.1158/0008-5472.CAN-20-0390",

language = "אנגלית",

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Pan, J, Silva, TC, Gull, N, Yang, Q, Plummer, JT, Chen, S, Daigo, K, Hamakubo, T, Gery, S, Ding, LW, Jiang, YY, Hu, S, Xu, LY, Li, EM, Ding, Y, Klempner, SJ, Gayther, SA, Berman, BP, Phillip Koeffler, H & Lin, DC 2020, 'Lineage-specific epigenomic and genomic activation of oncogene HNF4A promotes gastrointestinal adenocarcinomas', Cancer Research, vol. 80, no. 13, pp. 2722-2736. https://doi.org/10.1158/0008-5472.CAN-20-0390

TY - JOUR

T1 - Lineage-specific epigenomic and genomic activation of oncogene HNF4A promotes gastrointestinal adenocarcinomas

AU - Pan, Jian

AU - Silva, Tiago C.

AU - Gull, Nicole

AU - Yang, Qian

AU - Plummer, Jasmine T.

AU - Chen, Stephanie

AU - Daigo, Kenji

AU - Hamakubo, Takao

AU - Gery, Sigal

AU - Ding, Ling Wen

AU - Jiang, Yan Yi

AU - Hu, Shaoyan

AU - Xu, Li Yan

AU - Li, En Min

AU - Ding, Yanbing

AU - Klempner, Samuel J.

AU - Gayther, Simon A.

AU - Berman, Benjamin P.

AU - Phillip Koeffler, H.

AU - Lin, De Chen

PY - 2020/7/1

Y1 - 2020/7/1

N2 - Gastrointestinal adenocarcinomas (GIAC) of the tubular gastrointestinal (GI) tract including esophagus, stomach, colon, and rectum comprise most GI cancers and share a spectrum of genomic features. However, the unified epigenomic changes specific to GIAC are poorly characterized. Using 907 GIAC samples from The Cancer Genome Atlas, we applied mathematical algorithms to large-scale DNA methylome and transcriptome profiles to reconstruct transcription factor (TF) networks and identify a list of functionally hyperactive master regulator (MR) TF shared across different GIAC. The top candidate HNF4A exhibited prominent genomic and epigenomic activation in a GIAC-specific manner. A complex interplay between the HNF4A promoter and three distal enhancer elements was coordinated by GIAC-specific MRTF including ELF3, GATA4, GATA6, and KLF5. HNF4A also self-regulated its own promoter and enhancers. Functionally, HNF4A promoted cancer proliferation and survival by transcriptional activation of many downstream targets, including HNF1A and factors of interleukin signaling, in a lineage-specific manner. Overall, our study provides new insights into the GIAC-specific gene regulatory networks and identifies potential therapeutic strategies against these common cancers.

AB - Gastrointestinal adenocarcinomas (GIAC) of the tubular gastrointestinal (GI) tract including esophagus, stomach, colon, and rectum comprise most GI cancers and share a spectrum of genomic features. However, the unified epigenomic changes specific to GIAC are poorly characterized. Using 907 GIAC samples from The Cancer Genome Atlas, we applied mathematical algorithms to large-scale DNA methylome and transcriptome profiles to reconstruct transcription factor (TF) networks and identify a list of functionally hyperactive master regulator (MR) TF shared across different GIAC. The top candidate HNF4A exhibited prominent genomic and epigenomic activation in a GIAC-specific manner. A complex interplay between the HNF4A promoter and three distal enhancer elements was coordinated by GIAC-specific MRTF including ELF3, GATA4, GATA6, and KLF5. HNF4A also self-regulated its own promoter and enhancers. Functionally, HNF4A promoted cancer proliferation and survival by transcriptional activation of many downstream targets, including HNF1A and factors of interleukin signaling, in a lineage-specific manner. Overall, our study provides new insights into the GIAC-specific gene regulatory networks and identifies potential therapeutic strategies against these common cancers.

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AN - SCOPUS:85087474350

SN - 0008-5472

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EP - 2736

JO - Cancer Research

JF - Cancer Research

IS - 13

ER -

Lineage-specific epigenomic and genomic activation of oncogene HNF4A promotes gastrointestinal adenocarcinomas

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