Activation of bivalent factor DLX5 cooperates with master regulator TP63 to promote squamous cell carcinoma

Yongsheng Huang; Qian Yang; Yueyuan Zheng; Lehang Lin; Xin Xu; Xiu E. Xu; Tiago C. Silva; Masaharu Hazawa; Li Peng; Haotian Cao; Yanbing Ding; Daning Lu; Benjamin P. Berman; Li Yan Xu; En Min Li; Dong Yin

doi:10.1093/nar/gkab679

Activation of bivalent factor DLX5 cooperates with master regulator TP63 to promote squamous cell carcinoma

Yongsheng Huang, Qian Yang, Yueyuan Zheng, Lehang Lin, Xin Xu, Xiu E. Xu, Tiago C. Silva, Masaharu Hazawa, Li Peng, Haotian Cao, Yanbing Ding, Daning Lu, Benjamin P. Berman, Li Yan Xu^*, En Min Li^*, Dong Yin

^*Corresponding author for this work

Department of Developmental Biology and Cancer Research

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

13 Scopus citations

Abstract

To reconstruct systematically hyperactive transcription factor (TF)-dependent transcription networks in squamous cell carcinomas (SCCs), a computational method (ELMER) was applied to 1293 pan-SCC patient samples, and 44 hyperactive SCC TFs were identified. As a top candidate, DLX5 exhibits a notable bifurcate re-configuration of its bivalent promoter in cancer. Specifically, DLX5 maintains a bivalent state in normal tissues; its promoter is hypermethylation, leading to DLX5 transcriptional silencing in esophageal adenocarcinoma (EAC). In stark contrast, DLX5 promoter gains active histone marks and becomes transcriptionally activated in ESCC, which is directly mediated by SOX2. Functionally, silencing of DLX5 substantially inhibits SCC viability both in vitro and in vivo. Mechanistically, DLX5 cooperates with TP63 in regulating ∼2000 enhancers and promoters, which converge on activating cancer-promoting pathways. Together, our data establish a novel and strong SCC-promoting factor and elucidate a new epigenomic mechanism - bifurcate chromatin re-configuration - during cancer development.

Original language	English
Pages (from-to)	9246-9263
Number of pages	18
Journal	Nucleic Acids Research
Volume	49
Issue number	16
DOIs	https://doi.org/10.1093/nar/gkab679
State	Published - 20 Sep 2021

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© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.

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title = "Activation of bivalent factor DLX5 cooperates with master regulator TP63 to promote squamous cell carcinoma",

abstract = "To reconstruct systematically hyperactive transcription factor (TF)-dependent transcription networks in squamous cell carcinomas (SCCs), a computational method (ELMER) was applied to 1293 pan-SCC patient samples, and 44 hyperactive SCC TFs were identified. As a top candidate, DLX5 exhibits a notable bifurcate re-configuration of its bivalent promoter in cancer. Specifically, DLX5 maintains a bivalent state in normal tissues; its promoter is hypermethylation, leading to DLX5 transcriptional silencing in esophageal adenocarcinoma (EAC). In stark contrast, DLX5 promoter gains active histone marks and becomes transcriptionally activated in ESCC, which is directly mediated by SOX2. Functionally, silencing of DLX5 substantially inhibits SCC viability both in vitro and in vivo. Mechanistically, DLX5 cooperates with TP63 in regulating ∼2000 enhancers and promoters, which converge on activating cancer-promoting pathways. Together, our data establish a novel and strong SCC-promoting factor and elucidate a new epigenomic mechanism - bifurcate chromatin re-configuration - during cancer development.",

author = "Yongsheng Huang and Qian Yang and Yueyuan Zheng and Lehang Lin and Xin Xu and Xu, {Xiu E.} and Silva, {Tiago C.} and Masaharu Hazawa and Li Peng and Haotian Cao and Yanbing Ding and Daning Lu and Berman, {Benjamin P.} and Xu, {Li Yan} and Li, {En Min} and Dong Yin",

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doi = "10.1093/nar/gkab679",

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T1 - Activation of bivalent factor DLX5 cooperates with master regulator TP63 to promote squamous cell carcinoma

AU - Huang, Yongsheng

AU - Yang, Qian

AU - Zheng, Yueyuan

AU - Lin, Lehang

AU - Xu, Xin

AU - Xu, Xiu E.

AU - Silva, Tiago C.

AU - Hazawa, Masaharu

AU - Peng, Li

AU - Cao, Haotian

AU - Ding, Yanbing

AU - Lu, Daning

AU - Berman, Benjamin P.

AU - Xu, Li Yan

AU - Li, En Min

AU - Yin, Dong

PY - 2021/9/20

Y1 - 2021/9/20

N2 - To reconstruct systematically hyperactive transcription factor (TF)-dependent transcription networks in squamous cell carcinomas (SCCs), a computational method (ELMER) was applied to 1293 pan-SCC patient samples, and 44 hyperactive SCC TFs were identified. As a top candidate, DLX5 exhibits a notable bifurcate re-configuration of its bivalent promoter in cancer. Specifically, DLX5 maintains a bivalent state in normal tissues; its promoter is hypermethylation, leading to DLX5 transcriptional silencing in esophageal adenocarcinoma (EAC). In stark contrast, DLX5 promoter gains active histone marks and becomes transcriptionally activated in ESCC, which is directly mediated by SOX2. Functionally, silencing of DLX5 substantially inhibits SCC viability both in vitro and in vivo. Mechanistically, DLX5 cooperates with TP63 in regulating ∼2000 enhancers and promoters, which converge on activating cancer-promoting pathways. Together, our data establish a novel and strong SCC-promoting factor and elucidate a new epigenomic mechanism - bifurcate chromatin re-configuration - during cancer development.

AB - To reconstruct systematically hyperactive transcription factor (TF)-dependent transcription networks in squamous cell carcinomas (SCCs), a computational method (ELMER) was applied to 1293 pan-SCC patient samples, and 44 hyperactive SCC TFs were identified. As a top candidate, DLX5 exhibits a notable bifurcate re-configuration of its bivalent promoter in cancer. Specifically, DLX5 maintains a bivalent state in normal tissues; its promoter is hypermethylation, leading to DLX5 transcriptional silencing in esophageal adenocarcinoma (EAC). In stark contrast, DLX5 promoter gains active histone marks and becomes transcriptionally activated in ESCC, which is directly mediated by SOX2. Functionally, silencing of DLX5 substantially inhibits SCC viability both in vitro and in vivo. Mechanistically, DLX5 cooperates with TP63 in regulating ∼2000 enhancers and promoters, which converge on activating cancer-promoting pathways. Together, our data establish a novel and strong SCC-promoting factor and elucidate a new epigenomic mechanism - bifurcate chromatin re-configuration - during cancer development.

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Activation of bivalent factor DLX5 cooperates with master regulator TP63 to promote squamous cell carcinoma

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