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Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular

Agustin Sgro1,2,3, Joseph Cursons4, Charlene Waryah1,2

  • 1Cancer Epigenetics Group, The Harry Perkins Institute of Medical Research, Nedlands, Perth, WA, 6009, Australia.

Clinical Epigenetics
|April 29, 2023
PubMed
Abstract

Insights

CRISPR-activation (CRISPRa) reactivates silenced tumor suppressor genes in liver cancer. This approach offers a precise, personalized strategy to inhibit hepatocellular carcinoma progression.

Area of Science:

  • Oncology
  • Epigenetics
  • Gene Regulation

Background:

  • Epigenetic silencing of tumor suppressor genes (TSGs) is crucial in hepatocellular carcinoma (HCC) development.
  • CRISPR-activation (CRISPRa) systems enable targeted gene reactivation by exploiting chromatin plasticity.

Purpose of the Study:

  • To identify and target epigenetically silenced TSGs in HCC for therapeutic intervention.
  • To evaluate the efficacy of CRISPRa in reactivating multiple TSGs and inhibiting HCC progression.

Main Methods:

  • Analysis of The Cancer Genome Atlas HCC data to identify TSGs with promoter DNA methylation and low transcript abundance.
  • Development and application of CRISPRa systems for precise reactivation of selected TSGs in HCC cell lines.
  • Assessment of the impact of TSG reactivation on HCC cell viability, proliferation, and migration.

Main Results:

  • Identified 12 putative TSGs silenced in HCC, with most samples showing at least one silenced gene.
  • CRISPRa successfully reactivated at least 4 TSGs (HHIP, MT1M, PZP, TTC36) in Hep3B HCC cells.
  • Reactivation of these TSGs inhibited key aspects of HCC pathogenesis, including cell viability, proliferation, and migration.

Conclusions:

  • CRISPRa offers a potent and precise method for reactivating silenced TSGs in HCC.
  • A personalized treatment strategy using a panel of reactivated TSGs can potentially improve HCC patient outcomes.
  • A CRISPRa toolbox with multiple epigenetic effectors and guide RNAs is effective for patient-specific treatment of aggressive HCC.
Keywords:
CRISPRaEpigenetic drugsEpigenetic editing toolboxGenome multiplexingHepatocellular carcinomaPrecision medicineTumor suppressor genes

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