Deciphering the Roles of Cis-regulatory Elements and Retrotransposons in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the major form of primary liver cancer with limited therapeutic options. Epigenetic dysregulation plays an important role in the development of HCC; however, its impact on the transcriptional regulatory landscape remains incompletely understood.

In the first part of my study, I investigated the epigenetic changes that drive the aberrant activity of cis-regulatory elements (CREs) in HCC. I showed that focal DNA hypomethylation at promoters contributes to upregulation of cell cycle-related genes, whereas loss of DNA methylation in partially methylated domains is associated with downregulation of genes related to extracellular matrix organization. Notably, I discovered that both the reactivation of a super-enhancer and DNA hypomethylation of CpG islands are necessary for the transcriptional dysregulation of the glypican-3 (GPC3) gene, which encodes an immunotherapeutic target for HCC. This dual regulatory mechanism for GPC3 sheds light into the potential of incorporating DNA demethylating agent to enhance patient response to GPC3-targeted immunotherapies.

In the second part of my study, I examined the roles and clinical relevance of retrotransposon-driven transcripts in HCC. Retrotransposons are repetitive sequences that can produce transcripts with prognostic and immunotherapeutic implications in cancer. Specifically, I demonstrated that focal DNA hypomethylation drives the transcriptional derepression of a HERVE-int element-driven long non-coding RNA. Patients with high expression of this HERVE-int element have more aggressive tumors and exhibit molecular signatures associated with more favourable response to immunotherapy. These findings suggest HERVE-int as a potential prognostic biomarker and predictor of immunotherapy response for HCC.

Together, my work reveals the widespread epigenetic dysregulation of CREs and retrotransposons during hepatocarcinogenesis. Interrogating the aberrant epigenetic changes at these regulatory sequences highlights new potential therapeutic strategies and biomarkers for HCC.

Date of Award	2025
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Danny Chi Yeu LEUNG (Supervisor)