Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression

Yuan Jiang; Yan Yi Jiang; Jian Jun Xie; Anand Mayakonda; Masaharu Hazawa; Li Chen; Jin Fen Xiao; Chun Quan Li; Mo Li Huang; Ling Wen Ding; Qiao Yang Sun; Liang Xu; Deepika Kanojia; Maya Jeitany; Jian Wen Deng; Lian Di Liao; Harmik J. Soukiasian; Benjamin P. Berman; Jia Jie Hao; Li Yan Xu; En Min Li; Ming Rong Wang; Xin Gang Bi; De Chen Lin; H. Phillip Koeffler

doi:10.1038/s41467-018-06081-9

Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression

Yuan Jiang, Yan Yi Jiang, Jian Jun Xie, Anand Mayakonda, Masaharu Hazawa, Li Chen, Jin Fen Xiao, Chun Quan Li, Mo Li Huang, Ling Wen Ding, Qiao Yang Sun, Liang Xu, Deepika Kanojia, Maya Jeitany, Jian Wen Deng, Lian Di Liao, Harmik J. Soukiasian, Benjamin P. Berman, Jia Jie Hao, Li Yan XuEn Min Li, Ming Rong Wang, Xin Gang Bi, De Chen Lin, H. Phillip Koeffler

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

Abstract

Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that master transcription factors (TFs) TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. However, functional consequence of their frequent co-localization at super-enhancers remains incompletely understood. Here, epigenomic profilings of different types of SCCs reveal that TP63 and SOX2 cooperatively and lineage-specifically regulate long non-coding RNA (lncRNA) CCAT1 expression, through activation of its super-enhancers and promoter. Silencing of CCAT1 substantially reduces cellular growth both in vitro and in vivo, phenotyping the effect of inhibiting either TP63 or SOX2. ChIRP analysis shows that CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR expression by binding to the super-enhancers of EGFR, thereby activating both MEK/ERK1/2 and PI3K/AKT signaling pathways. These results together identify a SCC-specific DNA/RNA/protein complex which activates TP63/SOX2-CCAT1-EGFR cascade and promotes SCC tumorigenesis, advancing our understanding of transcription dysregulation in cancer biology mediated by master TFs and super-enhancers.

Original language	English
Article number	3619
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06081-9
State	Published - 1 Dec 2018
Externally published	Yes

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

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-018-06081-9

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Jiang, Y., Jiang, Y. Y., Xie, J. J., Mayakonda, A., Hazawa, M., Chen, L., Xiao, J. F., Li, C. Q., Huang, M. L., Ding, L. W., Sun, Q. Y., Xu, L., Kanojia, D., Jeitany, M., Deng, J. W., Liao, L. D., Soukiasian, H. J., Berman, B. P., Hao, J. J., ... Koeffler, H. P. (2018). Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression. Nature Communications, 9(1), Article 3619. https://doi.org/10.1038/s41467-018-06081-9

@article{81692e110e48403a91626c2edc5489a1,

title = "Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression",

abstract = "Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that master transcription factors (TFs) TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. However, functional consequence of their frequent co-localization at super-enhancers remains incompletely understood. Here, epigenomic profilings of different types of SCCs reveal that TP63 and SOX2 cooperatively and lineage-specifically regulate long non-coding RNA (lncRNA) CCAT1 expression, through activation of its super-enhancers and promoter. Silencing of CCAT1 substantially reduces cellular growth both in vitro and in vivo, phenotyping the effect of inhibiting either TP63 or SOX2. ChIRP analysis shows that CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR expression by binding to the super-enhancers of EGFR, thereby activating both MEK/ERK1/2 and PI3K/AKT signaling pathways. These results together identify a SCC-specific DNA/RNA/protein complex which activates TP63/SOX2-CCAT1-EGFR cascade and promotes SCC tumorigenesis, advancing our understanding of transcription dysregulation in cancer biology mediated by master TFs and super-enhancers.",

author = "Yuan Jiang and Jiang, \{Yan Yi\} and Xie, \{Jian Jun\} and Anand Mayakonda and Masaharu Hazawa and Li Chen and Xiao, \{Jin Fen\} and Li, \{Chun Quan\} and Huang, \{Mo Li\} and Ding, \{Ling Wen\} and Sun, \{Qiao Yang\} and Liang Xu and Deepika Kanojia and Maya Jeitany and Deng, \{Jian Wen\} and Liao, \{Lian Di\} and Soukiasian, \{Harmik J.\} and Berman, \{Benjamin P.\} and Hao, \{Jia Jie\} and Xu, \{Li Yan\} and Li, \{En Min\} and Wang, \{Ming Rong\} and Bi, \{Xin Gang\} and Lin, \{De Chen\} and Koeffler, \{H. Phillip\}",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-06081-9",

language = "الإنجليزيّة",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Jiang, Y, Jiang, YY, Xie, JJ, Mayakonda, A, Hazawa, M, Chen, L, Xiao, JF, Li, CQ, Huang, ML, Ding, LW, Sun, QY, Xu, L, Kanojia, D, Jeitany, M, Deng, JW, Liao, LD, Soukiasian, HJ, Berman, BP, Hao, JJ, Xu, LY, Li, EM, Wang, MR, Bi, XG, Lin, DC & Koeffler, HP 2018, 'Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression', Nature Communications, vol. 9, no. 1, 3619. https://doi.org/10.1038/s41467-018-06081-9

TY - JOUR

T1 - Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression

AU - Jiang, Yuan

AU - Jiang, Yan Yi

AU - Xie, Jian Jun

AU - Mayakonda, Anand

AU - Hazawa, Masaharu

AU - Chen, Li

AU - Xiao, Jin Fen

AU - Li, Chun Quan

AU - Huang, Mo Li

AU - Ding, Ling Wen

AU - Sun, Qiao Yang

AU - Xu, Liang

AU - Kanojia, Deepika

AU - Jeitany, Maya

AU - Deng, Jian Wen

AU - Liao, Lian Di

AU - Soukiasian, Harmik J.

AU - Berman, Benjamin P.

AU - Hao, Jia Jie

AU - Xu, Li Yan

AU - Li, En Min

AU - Wang, Ming Rong

AU - Bi, Xin Gang

AU - Lin, De Chen

AU - Koeffler, H. Phillip

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that master transcription factors (TFs) TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. However, functional consequence of their frequent co-localization at super-enhancers remains incompletely understood. Here, epigenomic profilings of different types of SCCs reveal that TP63 and SOX2 cooperatively and lineage-specifically regulate long non-coding RNA (lncRNA) CCAT1 expression, through activation of its super-enhancers and promoter. Silencing of CCAT1 substantially reduces cellular growth both in vitro and in vivo, phenotyping the effect of inhibiting either TP63 or SOX2. ChIRP analysis shows that CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR expression by binding to the super-enhancers of EGFR, thereby activating both MEK/ERK1/2 and PI3K/AKT signaling pathways. These results together identify a SCC-specific DNA/RNA/protein complex which activates TP63/SOX2-CCAT1-EGFR cascade and promotes SCC tumorigenesis, advancing our understanding of transcription dysregulation in cancer biology mediated by master TFs and super-enhancers.

AB - Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that master transcription factors (TFs) TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. However, functional consequence of their frequent co-localization at super-enhancers remains incompletely understood. Here, epigenomic profilings of different types of SCCs reveal that TP63 and SOX2 cooperatively and lineage-specifically regulate long non-coding RNA (lncRNA) CCAT1 expression, through activation of its super-enhancers and promoter. Silencing of CCAT1 substantially reduces cellular growth both in vitro and in vivo, phenotyping the effect of inhibiting either TP63 or SOX2. ChIRP analysis shows that CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR expression by binding to the super-enhancers of EGFR, thereby activating both MEK/ERK1/2 and PI3K/AKT signaling pathways. These results together identify a SCC-specific DNA/RNA/protein complex which activates TP63/SOX2-CCAT1-EGFR cascade and promotes SCC tumorigenesis, advancing our understanding of transcription dysregulation in cancer biology mediated by master TFs and super-enhancers.

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U2 - 10.1038/s41467-018-06081-9

DO - 10.1038/s41467-018-06081-9

M3 - مقالة

C2 - 30190462

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3619

ER -

Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression

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