# Crosstalk Between Cis-Regulatory Elements and Metabolism Reprogramming in Hepatocellular Carcinoma

## TL;DR

This review explores how genetic switches called CREs interact with metabolism in liver cancer, offering new therapeutic strategies.

## Contribution

The paper systematically summarizes the bidirectional crosstalk between CREs and metabolic reprogramming in hepatocellular carcinoma.

## Key findings

- CREs drive metabolic gene activation in HCC through mechanisms like enhancer hijacking and chromatin disruption.
- Metabolic intermediates like acetyl-CoA and lactate modulate CRE activity, creating feedback loops in cancer progression.
- Targeting oncogenic CREs could disrupt metabolic vulnerabilities for precision therapy in HCC.

## Abstract

Metabolic reprogramming is a fundamental hallmark of hepatocellular carcinoma (HCC), in which cis-regulatory elements (CREs) play a pivotal role. This review provides a systematic overview of the definition, identification, and biological functions of CREs in HCC-associated metabolic reprogramming. Aberrant CREs contribute substantially to tumorigenesis through multiple mechanisms, including promoter hypermethylation, enhancer hijacking and disruption of 3D chromatin organization. Furthermore, HCC progression is complicated by the bidirectional crosstalk between CREs and metabolic reprogramming. CREs orchestrate the transcription of core metabolic enzymes, while metabolic intermediates reciprocally fine-tune CRE activity by acting as substrates or cofactors for chromatin-modifying enzymes. Considering this interplay, novel therapeutic strategies aimed at targeting key oncogenic CREs may exploit CRE-metabolism vulnerabilities for better interventions in HCC.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, arising from profound metabolic reprogramming and widespread epigenetic dysregulation. However, the role of epigenetic aberrations in modulating metabolic reprogramming and the interplay between cis-regulatory elements (CREs), such as promoters, enhancers and super-enhancers, and metabolic adaptation have not been systematically summarized. Therefore, this review aims to integrate current evidence to elucidate the mechanisms of how cis-regulatory elements (CREs) drive oncogenic and metabolic signals in HCC progression. For instance, enhancers and super-enhancers transcriptionally activate key metabolic genes involved in aerobic glycolysis (GLUT1, HK2, PKM2, LDHA), de novo lipogenesis (ACLY, FASN, ACC), glutaminolysis (SLC1A5, GLS), and nucleotide synthesis. Meanwhile, many metabolic intermediates, including acetyl-CoA, succinyl-CoA and lactate, act as cofactors or substrates for epigenetic modifiers, creating bidirectional feedback loops that reinforce CRE-driven malignant phenotypes. Therefore, aberrant CREs acts as “metabolic switches” that sense and respond to various metabolic conditions to sustain HCC growth. Consequently, targeted intervention against oncogenic CREs, such as super-enhancers or their co-activators, to disrupt CRE-mediated metabolic vulnerabilities, has emerged as a highly promising new paradigm for precision therapy in HCC.