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MBD2 suppresses SFRP1 expression and promotes colorectal cancer development by blocking MED19 binding to its

Xiuji Huang1, Tingting Luo2, Lingling Ke2

  • 1Department of Respiratory and Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong, China.

Cancer Biology & Therapy
|May 5, 2026
PubMed
Abstract

Insights

MBD2 silences SFRP1 in colorectal cancer by blocking MED19 binding, independent of DNA methylation changes. Targeting MBD2 offers a new therapeutic strategy for CRC.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • SFRP1, a Wnt pathway antagonist, is epigenetically silenced in colorectal cancer (CRC) via promoter DNA hypermethylation.
  • MBD2, a DNA methylation reader, contributes to SFRP1 silencing, but its mechanism independent of methylation changes was unclear.
  • Understanding SFRP1 silencing mechanisms can identify novel therapeutic targets for CRC.

Purpose of the Study:

  • To elucidate the mechanism by which MBD2 suppresses SFRP1 expression.
  • To investigate the therapeutic potential of targeting MBD2 in colorectal cancer models.

Main Methods:

  • Inhibition of MBD2 using siRNA and a small molecule inhibitor (KCC07) in CRC models.
  • Assessment of SFRP1, β-catenin, Wnt pathway activity, cell proliferation, and apoptosis.
  • In vivo evaluation of tumor growth and mechanistic studies on MED19 binding and RNA polymerase II phosphorylation.

Main Results:

  • MBD2 inhibition (siRNA or KCC07) upregulated SFRP1, downregulated β-catenin, and suppressed Wnt signaling.
  • KCC07 treatment inhibited CRC cell proliferation, induced apoptosis, and reduced tumor growth in vivo.
  • MBD2 silences SFRP1 by preventing MED19 binding to the promoter, reducing RNA polymerase II CTD-S7 phosphorylation and impairing transcription.

Conclusions:

  • A novel mechanism of gene silencing by MBD2, independent of DNA methylation status, involves disruption of MED19 binding and transcription.
  • Targeting MBD2 presents a promising therapeutic strategy for colorectal cancer.
Keywords:
Colorectal cancerDNA methylationMBD2MED19SFRP1

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