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

Area of Science:

• Oncology
• Molecular Biology
• Gene Regulation

Background:

• The role of ETS variant 1 (ETV1), an oncogenic transcription factor, in colorectal cancer (CRC) is not well understood.
• ETV1 is implicated in various cancers, but its specific mechanisms in CRC require further elucidation.

Purpose of the Study:

• To investigate the role of ETV1 in colorectal cancer progression.
• To identify downstream targets and interacting proteins of ETV1 in CRC cells.
• To elucidate the functional consequences of ETV1 dysregulation in CRC.

Main Methods:

• Cell growth and clonogenic assays were performed to assess the impact of ETV1 downregulation.
• Quantitative PCR and Western blotting were used to measure gene and protein expression levels.
• Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) were employed to identify ETV1 binding sites and target genes.
• Reporter assays were conducted to analyze gene promoter activity.

Main Results:

• ETV1 downregulation reduced colorectal cancer cell growth and clonogenic activity.
• ETV1 mRNA levels were elevated in colorectal tumors and correlated with disease severity.
• ETV1 directly interacted with the histone demethylase JMJD1A, and they cooperatively activated the MMP1 and FOXQ1 gene promoters.
• RNA-seq identified FOXQ1 and TBX6 as potential ETV1 target genes; JMJD1A co-regulated FOXQ1 but not TBX6.
• FOXQ1 overexpression partially rescued ETV1 ablation-induced growth inhibition, while TBX6 impaired cell growth, suggesting a tumor-suppressive role.

Conclusions:

• A novel ETV1/JMJD1A-FOXQ1 signaling axis was identified, contributing to colorectal tumorigenesis.
• ETV1 acts as an oncogenic driver in CRC, promoting tumor growth and severity.
• TBX6 may function as a tumor suppressor in CRC, potentially counteracting ETV1's oncogenic effects.