HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer

Abstract

BackgroundWorldwide, gastric cancer (GC) is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects.ObjectiveTo determine oncogenic mechanisms and novel therapeutic targets specific for GC by identifying commonly dysregulated genes from the tumours of both Asian-Pacific and Caucasian patients.MethodsWe generated transcriptomic profiles of 22 Caucasian GC tumours and their matched non-cancerous samples and performed an integrative analysis across different GC gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signalling pathways by RNAi and/or pharmacological inhibition.ResultsHepatocyte nuclear factor-4α (HNF4α) upregulation was a key signalling event in gastric tumours from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumour cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signalling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest and tumour growth inhibition. HNF4α also regulated WNT signalling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumours.ConclusionsOur results indicate that HNF4α is a targetable oncoprotein in GC, is regulated by AMPK signalling through AMPKα and resides upstream of WNT signalling. HNF4α may regulate ‘metabolic switch’ characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signalling cascade represents a potentially targetable pathway for drug development.

Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma

“…S6). For example, HNF4A, a transcription factor overexpressed in gastric cancer (58)(59)(60)(61), is driven by two promoters (P1 and P2). At the HNF4A canonical promoter ("P2"), we observed equal promoter signals in gastric cancer tissues and normal tissues; however, we also further observed gain of an additional promoter in gastric cancers at a TSS 45 kb downstream ("P1").…”

WNT5A Correlates with Clinicopathological Characteristics in Gastric Cancer: a Meta-Analysis

“…In cancer, diverse studies of WNT5A show that its expression associates with clinicopathological characteristics [7]. Also, our previous study reported WNT5A expression associated with the Lauren classification of GC [8].…”

“…Information of cohorts eligible for our meta-analysis of WNT5A in gastric cancer. Chang et al [8] previously reported two independent cohorts: one for discovery (henceforth, Chang_D), and the other for validation (henceforth; Chang_V). In our meta-analysis, we used the two cohorts separately.…”

“…As a result, four publications (Table 1) were selected for meta-analysis. One study [8] had two independent cohorts, and a total of five cohorts/datasets were eligible for our meta-analysis ( Table 1). The selection processes are depicted in Fig 1. Expression of WNT5A was measured through immunohistochemistry (IHC).…”

Differential Effects of Hepatocyte Nuclear Factor 4α Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells

“…The Cancer Genome Atlas (TCGA) recently identified the region encompassing HNF4A (20q13.12) as being one of several amplified loci in over 255 human colon cancers (36) and found an overexpression of the HNF4␣ protein in a subset of those samples (37). HNF4␣ has also been shown to exhibit oncogenic activity in gastric cancer (38). While these findings suggest that the HNF4␣ gene may act as an oncogene, as well as a tumor suppressor, the relative contributions of the different HNF4␣ isoforms were not determined.…”