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

• Published in: Clinical epigenetics Vol. 15; no. 1; p. 73
• Main Authors: Sgro, Agustin, Cursons, Joseph, Waryah, Charlene, Woodward, Eleanor A, Foroutan, Momeneh, Lyu, Ruqian, Yeoh, George C T, Leedman, Peter J, Blancafort, Pilar
• Format: Journal Article
• Language: English
• Published: Germany BioMed Central Ltd 29.04.2023; BioMed Central; BMC
• Subjects: Antimitotic agents; Antineoplastic agents; Breast cancer; Cancer; Cancer therapies; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell cycle; Cell Line, Tumor; Cell migration; Cell proliferation; Cell viability; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; CRISPR; CRISPRa; Development and progression; DNA Methylation; Drug resistance; Epigenesis, Genetic; Epigenetic drugs; Epigenetic editing toolbox; Epigenetic inheritance; Epigenetics; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genes, Tumor Suppressor; Genetic aspects; Genetic transcription; Genome multiplexing; Genomes; Genomics; Hepatocellular carcinoma; Hepatoma; Humans; Kinases; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Medical prognosis; Methylation; Mutation; Pathogenesis; Patients; Scientific equipment and supplies industry; Tumor suppressor genes; Tumorigenesis; Tumors; Australia; United States; Precision medicine; Epigenetic drugs; Epigenetic editing toolbox; Hepatocellular carcinoma; Tumor suppressor genes; Genome multiplexing; CRISPRa
• ISSN: 1868-7083; 1868-7075; 1868-7083; 1868-7075
• DOI: 10.1186/s13148-023-01482-0

Epigenetic silencing of tumor suppressor genes (TSGs) is a key feature of oncogenesis in hepatocellular carcinoma (HCC). Liver-targeted delivery of CRISPR-activation (CRISPRa) systems makes it possible to exploit chromatin plasticity, by reprogramming transcriptional dysregulation. Using The Cancer Genome Atlas HCC data, we identify 12 putative TSGs with negative associations between promoter DNA methylation and transcript abundance, with limited genetic alterations. All HCC samples harbor at least one silenced TSG, suggesting that combining a specific panel of genomic targets could maximize efficacy, and potentially improve outcomes as a personalized treatment strategy for HCC patients. Unlike epigenetic modifying drugs lacking locus selectivity, CRISPRa systems enable potent and precise reactivation of at least 4 TSGs tailored to representative HCC lines. Concerted reactivation of HHIP, MT1M, PZP, and TTC36 in Hep3B cells inhibits multiple facets of HCC pathogenesis, such as cell viability, proliferation, and migration. By combining multiple effector domains, we demonstrate the utility of a CRISPRa toolbox of epigenetic effectors and gRNAs for patient-specific treatment of aggressive HCC.