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

Xun Chen1, Qian Zhang2, Xiaoqian Dang3

  • 1Department of Orthopaedics, Honghui Hospital, Xi'an Jiaotong University, 76 Nanguo Rd, Beilin District, Xi'an, Shaanxi 710054, China; Department of Orthopaedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710005, China.

Translational Oncology
|April 22, 2022
PubMed

Insights

C-terminal binding protein (CtBP) interacting protein (CtIP) forms a complex that regulates DNA repair genes MLH1, MSH3, BRCA1, and CDKN1A. Inhibiting this complex slows osteosarcoma cell growth.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Tumors, including osteosarcomas, often exhibit impaired DNA damage repair.
  • Mechanisms regulating DNA damage repair gene expression are under active investigation.

Purpose of the Study:

  • To elucidate the regulatory mechanisms controlling key DNA damage and repair genes in osteosarcoma.
  • To identify the role of the CtBP interacting protein (CtIP) in regulating these genes.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) assays to identify gene promoter binding.
  • Gene expression analysis upon depletion or overexpression of key proteins.
  • In vitro and in vivo assays to assess osteosarcoma cell growth and tumor progression.

Main Results:

  • CtIP, CtBP1/2, HDAC1, and AP1 form a transcriptional complex regulating MLH1, MSH3, BRCA1, and CDKN1A.
  • This complex binds to the TGAT/CTCA consensus sequence in the promoters of these four genes.
  • Depletion of CtIP, CtBP1/2, or HDAC1 upregulated MLH1, MSH3, BRCA1, and CDKN1A, inhibiting osteosarcoma cell growth.
  • Overexpression of MLH1, MSH3, BRCA1, or CDKN1A reduced osteosarcoma cell viability, migration, and tumor growth.

Conclusions:

  • The CtIP-CtBP1/2-HDAC1-AP1 complex is crucial for mediating DNA damage repair processes in osteosarcoma pathogenesis.
  • Targeting this complex or its downstream genes presents a potential therapeutic strategy for osteosarcoma.
Keywords:
AP1, DNA damageCtBP1CtBP2CtIPOsteosarcoma

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