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The CtIP-CtBP1/2-HDAC1-AP1 transcriptional complex is required for the transrepression of DNA damage modulators in the pathogenesis of osteosarcoma

Most tumors, including osteosarcomas, have deficiencies in DNA damage repair. However, the regulatory mechanisms underlying dysregulation of DNA damage repair genes are still being investigated. In this study, we reveal that C-terminal binding protein (CtBP) interacting protein (CtIP) couples with t...

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Autores principales: Chen, Xun, Zhang, Qian, Dang, Xiaoqian, Fan, Jinzhu, Song, Tao, Li, Zhong, Duan, Ning, Zhang, Wentao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9047009/
https://www.ncbi.nlm.nih.gov/pubmed/35452995
http://dx.doi.org/10.1016/j.tranon.2022.101429
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author Chen, Xun
Zhang, Qian
Dang, Xiaoqian
Fan, Jinzhu
Song, Tao
Li, Zhong
Duan, Ning
Zhang, Wentao
author_facet Chen, Xun
Zhang, Qian
Dang, Xiaoqian
Fan, Jinzhu
Song, Tao
Li, Zhong
Duan, Ning
Zhang, Wentao
author_sort Chen, Xun
collection PubMed
description Most tumors, including osteosarcomas, have deficiencies in DNA damage repair. However, the regulatory mechanisms underlying dysregulation of DNA damage repair genes are still being investigated. In this study, we reveal that C-terminal binding protein (CtBP) interacting protein (CtIP) couples with three transcriptional regulators, CtBP1/2 heterodimer, histone deacetylase 1 (HDAC1), and two subunits of the activating protein 1 (AP1) transcription factor to assemble a transcriptional complex. This complex specifically controls the expression of four genes involved in DNA damage and repair processes: MutL homolog 1 (MLH1), MutS Homolog 3 (MSH3), breast cancer type 1 (BRCA1), and cyclin dependent kinase inhibitor 1A (CDKN1A). Chromatin immunoprecipitation (ChIP) assay results revealed that the CtIP-CtBP1/2-HDAC1-AP1 complex regulated these four genes by binding to their promoters through the TGAT/CTCA consensus sequence. The depletion of CtIP, CtBP1/2, and HDAC1 increased the expression levels of MLH1, MSH3, BRCA1, and CDKN1A and inhibited in vitro and in vivo osteosarcoma cell growth. Overexpression of MLH1, MSH3, BRCA1, or CDKN1A in osteosarcoma cells can reduce cell viability, colony formation, cell migration, and tumor growth. Our findings suggest that the CtIP-CtBP1/2-HDAC1-AP1 complex is required for mediation of DNA damage processes for the pathogenesis of osteosarcoma.
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spelling pubmed-90470092022-05-03 The CtIP-CtBP1/2-HDAC1-AP1 transcriptional complex is required for the transrepression of DNA damage modulators in the pathogenesis of osteosarcoma Chen, Xun Zhang, Qian Dang, Xiaoqian Fan, Jinzhu Song, Tao Li, Zhong Duan, Ning Zhang, Wentao Transl Oncol Original Research Most tumors, including osteosarcomas, have deficiencies in DNA damage repair. However, the regulatory mechanisms underlying dysregulation of DNA damage repair genes are still being investigated. In this study, we reveal that C-terminal binding protein (CtBP) interacting protein (CtIP) couples with three transcriptional regulators, CtBP1/2 heterodimer, histone deacetylase 1 (HDAC1), and two subunits of the activating protein 1 (AP1) transcription factor to assemble a transcriptional complex. This complex specifically controls the expression of four genes involved in DNA damage and repair processes: MutL homolog 1 (MLH1), MutS Homolog 3 (MSH3), breast cancer type 1 (BRCA1), and cyclin dependent kinase inhibitor 1A (CDKN1A). Chromatin immunoprecipitation (ChIP) assay results revealed that the CtIP-CtBP1/2-HDAC1-AP1 complex regulated these four genes by binding to their promoters through the TGAT/CTCA consensus sequence. The depletion of CtIP, CtBP1/2, and HDAC1 increased the expression levels of MLH1, MSH3, BRCA1, and CDKN1A and inhibited in vitro and in vivo osteosarcoma cell growth. Overexpression of MLH1, MSH3, BRCA1, or CDKN1A in osteosarcoma cells can reduce cell viability, colony formation, cell migration, and tumor growth. Our findings suggest that the CtIP-CtBP1/2-HDAC1-AP1 complex is required for mediation of DNA damage processes for the pathogenesis of osteosarcoma. Neoplasia Press 2022-04-19 /pmc/articles/PMC9047009/ /pubmed/35452995 http://dx.doi.org/10.1016/j.tranon.2022.101429 Text en © 2022 The Authors. Published by Elsevier Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Chen, Xun
Zhang, Qian
Dang, Xiaoqian
Fan, Jinzhu
Song, Tao
Li, Zhong
Duan, Ning
Zhang, Wentao
The CtIP-CtBP1/2-HDAC1-AP1 transcriptional complex is required for the transrepression of DNA damage modulators in the pathogenesis of osteosarcoma
title The CtIP-CtBP1/2-HDAC1-AP1 transcriptional complex is required for the transrepression of DNA damage modulators in the pathogenesis of osteosarcoma
title_full The CtIP-CtBP1/2-HDAC1-AP1 transcriptional complex is required for the transrepression of DNA damage modulators in the pathogenesis of osteosarcoma
title_fullStr The CtIP-CtBP1/2-HDAC1-AP1 transcriptional complex is required for the transrepression of DNA damage modulators in the pathogenesis of osteosarcoma
title_full_unstemmed The CtIP-CtBP1/2-HDAC1-AP1 transcriptional complex is required for the transrepression of DNA damage modulators in the pathogenesis of osteosarcoma
title_short The CtIP-CtBP1/2-HDAC1-AP1 transcriptional complex is required for the transrepression of DNA damage modulators in the pathogenesis of osteosarcoma
title_sort ctip-ctbp1/2-hdac1-ap1 transcriptional complex is required for the transrepression of dna damage modulators in the pathogenesis of osteosarcoma
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9047009/
https://www.ncbi.nlm.nih.gov/pubmed/35452995
http://dx.doi.org/10.1016/j.tranon.2022.101429
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