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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2022
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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. |
format | Online Article Text |
id | pubmed-9047009 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
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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