Silencing speckle-type POZ protein by promoter hypermethylation decreases cell apoptosis through upregulating Hedgehog signaling pathway in colorectal cancer

Cell Death Dis. 2016 Dec 29;7(12):e2569. doi: 10.1038/cddis.2016.435.

Abstract

Epigenetic silencing of tumor suppressors contributes to the development and progression of colorectal cancer (CRC). We recently found that speckle-type POZ protein (SPOP) was significantly downregulated and the inactivation of SPOP promoted metastasis in CRC. This study aimed to clarify its epigenetic alteration, molecular mechanisms and clinical significance in CRC. Our results revealed that the core region of SPOP promoter was hypermethylated in CRC tissues and its methylation was correlated with poor survival. Transcription factor RXRA had a vital role in the regulation of SPOP gene. The data indicated that DNA methylation at -167 bp of the SPOP gene altered the binding affinity between transcription factor RXRA and SPOP promoter. Moreover, SPOP was found to associate with Gli2 and promoted its ubiquitination and degradation in CRC. Consequently, the expression level of Hh/Gli2 pathway-related apoptotic protein Bcl-2 was decreased and the function of resisting cell death was inhibited in CRC. It suggests that methylation status of SPOP promoter can be used as a novel epigenetic biomarker and a therapeutic target in CRC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Anoikis / genetics
  • Apoptosis / genetics*
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / genetics*
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • Female
  • Gene Silencing*
  • Hedgehog Proteins / metabolism*
  • Humans
  • Kruppel-Like Transcription Factors / metabolism
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Promoter Regions, Genetic*
  • Protein Binding / genetics
  • Proteolysis
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Retinoid X Receptor alpha / metabolism
  • Signal Transduction / genetics
  • Transcription, Genetic
  • Ubiquitination
  • Up-Regulation / genetics*
  • Zinc Finger Protein Gli2

Substances

  • GLI2 protein, human
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Nuclear Proteins
  • Repressor Proteins
  • Retinoid X Receptor alpha
  • SPOP protein, human
  • Zinc Finger Protein Gli2