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Oncogenic STRAP functions as a novel negative regulator of E-cadherin and p21(Cip1) by modulating the transcription

Lin Jin1, Pran K Datta

  • 1a Division of Hematology and Oncology; Department of Medicine; UAB Comprehensive Cancer Center; University of Alabama at Birmingham ; Birmingham , AL USA.

Cell Cycle (Georgetown, Tex.)
|December 9, 2014
PubMed

Insights

STRAP protein downregulates E-cadherin and p21(Cip1) by inhibiting Sp1 transcription. Loss of STRAP stabilizes Sp1, increasing p21(Cip1) and arresting cell cycle, suggesting STRAP

Area of Science:

  • Molecular and Cellular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • STRAP (STRA6-interacting protein) is a novel WD-domain protein.
  • STRAP influences mesenchymal morphology, E-cadherin regulation, and tumorigenicity.
  • The precise mechanism by which STRAP regulates E-cadherin and p21(Cip1) remains unclear.

Purpose of the Study:

  • To elucidate the functional mechanism of STRAP in regulating E-cadherin and p21(Cip1).
  • To investigate STRAP's role in Sp1-dependent transcription and its implications in cancer.

Main Methods:

  • Utilized STRAP knockout and knockdown cell models (mouse embryonic fibroblast, human cancer cell lines).
  • Performed Chromatin Immunoprecipitation (ChIP) assays.
  • Conducted Bioinformatics and Microarray analyses.
  • Analyzed Sp1 binding and ubiquitination.
  • Correlated STRAP and Sp1 expression in Non-Small Cell Lung Cancer (NSCLC).

Main Results:

  • STRAP downregulates E-cadherin and p21(Cip1) by abrogating Sp1 binding to consensus sites.
  • STRAP recruits HDAC1 to Sp1 binding sites in the p21(Cip1) promoter.
  • Loss of STRAP stabilizes Sp1 by inhibiting ubiquitination, leading to >4.5-fold p21(Cip1) increase and cell cycle arrest.
  • 87% of STRAP-downregulated mouse genes possess conserved Sp1 binding sites.
  • STRAP expression inversely correlates with Sp1 levels in 60% of NSCLC cases.

Conclusions:

  • STRAP regulates E-cadherin and p21(Cip1) via a novel mechanism involving Sp1-dependent transcription modulation.
  • Elevated STRAP expression in lung cancer may promote tumor progression by downregulating E-cadherin and p21(Cip1).
  • STRAP represents a potential therapeutic target in lung cancer.
Keywords:
CDK2, cyclin-dependent kinase 2CDK4, cyclin-dependent kinase 4HDAC1, histone deacetylase 1HDAC2, histone deacetylase 2HDAC3, histone deacetylase 3HNF4, hepatocyte nuclear factor 4MEF, mouse embryonic fibroblastNF-YA, nuclear transcription factor Y subunit alphaPARP, poly (ADP-ribose) polymeraseRNase, A ribonuclease ARhoA, Ras homolog gene family, member ASTRAPSTRAP, serine threonine kinase receptor-associated proteinSWI/SNF, SWItch/Sucrose nonfermentableSp/KLF, specificity protein/Krüppel-like factorSp1Sp1, specificity protein 1TSA, trichostatin ATSS, transcription start siteTβR I, II, TGF-β receptor I, IIcell cyclep300/CBP, p300/ CREB-binding proteintranscription factorubiquitination

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