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

IF 5.7 2区 医学 Q1 Medicine
Agustin Sgro, Joseph Cursons, Charlene Waryah, Eleanor A Woodward, Momeneh Foroutan, Ruqian Lyu, George C T Yeoh, Peter J Leedman, Pilar Blancafort
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引用次数: 1

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.

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利用CRISPRa技术实现肿瘤抑制基因的表观遗传再激活作为肝癌的精准治疗。
背景:肿瘤抑制基因(TSGs)的表观遗传沉默是肝细胞癌(HCC)发生的一个关键特征。肝脏靶向递送crispr激活(CRISPRa)系统使得利用染色质可塑性成为可能,通过重编程转录失调。结果:利用肝癌基因组图谱数据,我们确定了12个假定的tsg,它们在启动子DNA甲基化和转录物丰度之间存在负相关,遗传改变有限。所有HCC样本都含有至少一个沉默的TSG,这表明结合一组特定的基因组靶点可以最大限度地提高疗效,并有可能改善HCC患者的个性化治疗策略。与缺乏基因座选择性的表观遗传修饰药物不同,CRISPRa系统能够有效和精确地重新激活至少4种针对代表性HCC细胞系的tsg。Hep3B细胞中的HHIP、MT1M、PZP和TTC36协同再激活可抑制HCC发病机制的多个方面,如细胞活力、增殖和迁移。结论:通过结合多个效应域,我们证明了表观遗传效应和grna的CRISPRa工具箱在侵袭性HCC患者特异性治疗中的实用性。
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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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