Histone demethylase Jumonji domain-containing 1A inhibits proliferation and progression of gastric cancer by upregulating runt-related transcription factor 3

Abstract

The histone demethylase Jumonji domain-containing 1A (JMJD1A) is overexpressed in multiple cancers and promotes cancer progression. However, the role and mechanism of JMJD1A in gastric cancer (GC) remains poorly understood. Here, we found that JMJD1A could suppress GC cell proliferation and xenograft tumor growth. Using RNA sequencing, we identified runt-related transcription factor 3 (RUNX3) as a novel target gene of JMJD1A. Mechanistically, we identified that JMJD1A upregulated RUNX3 through co-activating Ets-1 and reducing the H3K9me1/2 levels at the RUNX3 promoter in GC cells. Functionally, JMJD1A inhibits the growth of GC cells in vivo, which is partially dependent on RUNX3. Moreover, JMJD1A expression was decreased in GC and low expression of JMJD1A was correlated with an aggressive phenotype and a poor prognosis in patients with GC. Importantly, JMJD1A expression was positively associated with RUNX3 expression in GC samples. These studies indicated that JMJD1A upregulates RUNX3 expression via co-activation of transcription factor Ets-1 to inhibit proliferation of GC cells. Our findings provide new insight into the mechanism by which JMJD1A regulates RUNX3 transcription and suggest that JMJD1A and/or RUNX3 may be used as a therapeutic intervention for GC.

Keywords: Ets-1; JMJD1A; RUNX3; histone demethylase; transcriptional regulation.