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Targeted demethylation of the SARI promotor impairs colon tumour growth

Qin Wang1, Lei Dai1, Yuan Wang1

  • 1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, 610041, PR China.

Cancer Letters
|February 17, 2019
PubMed

Insights

DNA methylation inactivates the SARI tumor suppressor in colon cancer. A novel demethylation system restored SARI expression and demonstrated anti-tumor effects, offering a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • SARI (suppressor of activator protein 1, regulated by IFN) is a tumor suppressor frequently inactivated in various cancers.
  • The precise mechanisms of SARI inactivation in cancer, particularly colon cancer, remain largely unknown.

Purpose of the Study:

  • To investigate the role of SARI promoter DNA methylation in colon cancer.
  • To develop and evaluate a targeted epigenetic therapy for SARI reactivation in colon cancer.

Main Methods:

  • Analysis of SARI promoter methylation and expression in colon cancer patient tissues.
  • Development of a dCas9-based demethylation system (dCas9-multiGCN4/scFv-TET1CD-sgSARI) targeting the SARI promoter.
  • In vitro and in vivo evaluation of the anti-tumor efficacy of the demethylation system.

Main Results:

  • High SARI promoter methylation and inverse correlation with SARI expression were observed in colon cancer tissues.
  • SARI promoter methylation status served as a prognostic indicator for colon cancer patients.
  • The dCas9-multiGCN4/scFv-TET1CD-sgSARI system effectively demethylated the SARI promoter, significantly activating SARI expression.
  • Targeted SARI demethylation demonstrated significant anti-tumor effects by inhibiting proliferation, promoting apoptosis, and reducing angiogenesis.

Conclusions:

  • Epigenetic silencing via SARI promoter methylation contributes to colon cancer progression.
  • Targeted demethylation and restoration of SARI expression using the dCas9-based system show therapeutic potential for colon cancer.
  • This approach may also be applicable to other cancers where SARI is epigenetically silenced.
Keywords:
Colon cancerMethylationSARITET1dCas9

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