# HNF4α-HKDC1 axis orchestrates a metabolic rewiring to promote migration and metastasis in advanced gastric cancer

## TL;DR

This study identifies a new pathway involving HNF4α and HKDC1 that promotes gastric cancer metastasis and suggests a potential treatment using an existing drug.

## Contribution

The study reveals the HNF4α-HKDC1 axis as a novel driver of gastric cancer metastasis and a potential therapeutic target.

## Key findings

- P2-HNF4α is highly expressed in metastatic gastric cancer and promotes cell migration and metastasis.
- HNF4α activates HKDC1, which rewires metabolism to support cancer progression.
- Mycophenolic acid inhibits HKDC1 and reduces cancer migration and metastasis in models.

## Abstract

Metastatic gastric cancer (GC) has a poor prognosis. Recent research demonstrated the aberrant expression of nuclear receptor HNF4α and the regulatory roles of its isoforms during the processes of tumorigenesis and development. However, the expression patterns of HNF4α and its potential as a therapeutic target in metastatic GC remain elusive. In this study, we unveiled that P2 promoter-driven HNF4α (P2-HNF4α) was highly expressed in distant metastasis of GC, playing a pivotal role in fostering the migration and metastasis of GC cells both in vitro and in vivo. The transactivational activity was essential for HNF4α to promote GC cell migration. An integrative analysis of transcriptome and metabolome implied the involvement of the glycolytic pathway in the promotion of GC cell migration by P2-HNF4α. We further found that P2-HNF4α directly bound to the enhancer of the HKDC1 gene and upregulated its expression, thereby orchestrating a metabolic rewiring conducive to promoting GC migration and metastasis. Mycophenolic acid, an active metabolite of the FDA-approved drug mycophenolate mofetil, demonstrated the ability to suppress HKDC1 expression and GC migration and metastasis in vitro and in vivo through antagonizing HNF4α. Therefore, this study sheds light on the HNF4α-HKDC1 axis as a key player in GC metastasis, providing a promising targeted therapeutic strategy for metastatic GC.