Cooperation between ETS transcription factor ETV1 and histone demethylase JMJD1A in colorectal cancer

Abstract

ETS variant 1 (ETV1) is an oncogenic transcription factor. However, its role in colorectal cancer has remained understudied. The present study demonstrated that ETV1 downregulation led to reduced HCT116 colorectal cancer cell growth and clonogenic activity. Furthermore, the ETV1 mRNA levels were enhanced in colorectal tumors and were associated with disease severity. In addition, ETV1 directly bound to Jumonji C domain-containing (JMJD) 1A, a histone demethylase known to promote colon cancer. ETV1 and JMJD1A, but not a catalytically inactive mutant thereof, cooperated in inducing the matrix metalloproteinase (MMP)1 gene promoter that was similar to the cooperation between ETV1 and another histone demethylase, JMJD2A. RNA-sequencing revealed multiple potential ETV1 target genes in HCT116 cells, including the FOXQ1 and TBX6 transcription factor genes. Moreover, JMJD1A co-regulated FOXQ1 and other ETV1 target genes, but not TBX6, whereas JMJD2A downregulation had no impact on FOXQ1 as well as TBX6 transcription. Accordingly, the FOXQ1 gene promoter was stimulated by ETV1 and JMJD1A in a cooperative manner, and both ETV1 and JMJD1A bound to the FOXQ1 promoter. Notably, the overexpression of FOXQ1 partially reversed the growth inhibitory effects of ETV1 ablation on HCT116 cells, whereas TBX6 impaired HCT116 cell growth and may thereby dampen the oncogenic activity of ETV1. The latter also revealed for the first time, to the best of our knowledge, a potential tumor suppressive function of TBX6. Taken together, the present study uncovered a ETV1/JMJD1A-FOXQ1 axis that may drive colorectal tumorigenesis.

An Early-Onset Advanced Rectal Cancer Patient With Increased KRAS Gene Copy Number Showed A Primary Resistance to Cetuximab in Combination With Chemotherapy: A Case Report

“…Furthermore, blood-based NGS testing suggested lowabundance mutations (<5%) of nine newly emerged genes, indicating the emergence of tumor subcloning and heterogeneity. These genes have been previously reported to be associated with poor prognosis (21)(22)(23)(24)(25)(26)(27), but few reports on the efficacy of chemotherapy or target drugs are available. This suggests that tumors with polygenic mutations tend to be more aggressive in terms of biological behavior, leading to poor survival rates.…”

ETV1 Positively Correlated With Immune Infiltration and Poor Clinical Prognosis in Colorectal Cancer

“…ETV1 could be upregulated by BRAFV600E/MAPK pathway activation to promote cancer invasiveness and progression (38). Oh et al (39) revealed that ETV1 may regulate JMJD1A-FOXQ1 axis to drive colorectal tumorigenesis. In skin squamous cell carcinomas, upregulation of ETV1 was sufficient to induce most CAF effectors upregulated by fibroblast growth factor (FGF), which could promote the secretion of multiple chemokines with macrophagerecruiting activity including CXCL1, CXCL10, and CXCL11.…”

Histone demethylase JMJD1A in cancer progression and therapeutic resistance

“…Finally, JMJD1A can also function as a coactivator for ETS transcription factor ETV1 to promote the colorectal tumorigenesis. 28 In HeLa cells derived from cervical cancer, JMJD1A can function as a coactivator for signal transducer and activator of transcription 3 (STAT3) and promote the recruitment of STAT3 to the c-Myc gene promoter through H3K9 demethylation. Thus, JMJD1A can promote the JAK2-STAT3 signaling to promote the proliferation and motility of HeLa cells.…”