Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma
Abstract Background 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 dysregulatio...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-04-01
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| Series: | Clinical Epigenetics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13148-023-01482-0 |
| _version_ | 1797836412206186496 |
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| author | Agustin Sgro Joseph Cursons Charlene Waryah Eleanor A. Woodward Momeneh Foroutan Ruqian Lyu George C. T. Yeoh Peter J. Leedman Pilar Blancafort |
| author_facet | Agustin Sgro Joseph Cursons Charlene Waryah Eleanor A. Woodward Momeneh Foroutan Ruqian Lyu George C. T. Yeoh Peter J. Leedman Pilar Blancafort |
| author_sort | Agustin Sgro |
| collection | DOAJ |
| description | Abstract Background 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. Results 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. Conclusions 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. |
| first_indexed | 2024-04-09T15:08:28Z |
| format | Article |
| id | doaj.art-57f17a1387644e289dd4a0fa2cd044ff |
| institution | Directory Open Access Journal |
| issn | 1868-7083 |
| language | English |
| last_indexed | 2024-04-09T15:08:28Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj.art-57f17a1387644e289dd4a0fa2cd044ff2023-04-30T11:19:19ZengBMCClinical Epigenetics1868-70832023-04-0115112410.1186/s13148-023-01482-0Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinomaAgustin Sgro0Joseph Cursons1Charlene Waryah2Eleanor A. Woodward3Momeneh Foroutan4Ruqian Lyu5George C. T. Yeoh6Peter J. Leedman7Pilar Blancafort8Cancer Epigenetics Group, The Harry Perkins Institute of Medical ResearchBiomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash UniversityCancer Epigenetics Group, The Harry Perkins Institute of Medical ResearchCancer Epigenetics Group, The Harry Perkins Institute of Medical ResearchBiomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash UniversityBioinformatics and Cellular Genomics, St Vincent’s Institute of Medical ResearchCentre for Medical Research, The University of Western AustraliaCentre for Medical Research, The University of Western AustraliaCancer Epigenetics Group, The Harry Perkins Institute of Medical ResearchAbstract Background 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. Results 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. Conclusions 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.https://doi.org/10.1186/s13148-023-01482-0CRISPRaGenome multiplexingEpigenetic editing toolboxTumor suppressor genesHepatocellular carcinomaEpigenetic drugs |
| spellingShingle | Agustin Sgro Joseph Cursons Charlene Waryah Eleanor A. Woodward Momeneh Foroutan Ruqian Lyu George C. T. Yeoh Peter J. Leedman Pilar Blancafort Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma Clinical Epigenetics CRISPRa Genome multiplexing Epigenetic editing toolbox Tumor suppressor genes Hepatocellular carcinoma Epigenetic drugs |
| title | Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma |
| title_full | Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma |
| title_fullStr | Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma |
| title_full_unstemmed | Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma |
| title_short | Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma |
| title_sort | epigenetic reactivation of tumor suppressor genes with crispra technologies as precision therapy for hepatocellular carcinoma |
| topic | CRISPRa Genome multiplexing Epigenetic editing toolbox Tumor suppressor genes Hepatocellular carcinoma Epigenetic drugs |
| url | https://doi.org/10.1186/s13148-023-01482-0 |
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