KMT2A Histone Methyltransferase Contributes to Intrahepatic Cholangiocarcinoma Cell Growth by Promoting JAK2 Transcriptional Activation.

Abstract

Introduction: Intrahepatic cholangiocarcinoma (ICC) is known for its aggressive behavior and poor prognosis, but the role of dysregulated KMT2A in this cancer is not well understood. The study aimed to determine whether KMT2A functions as an oncogene in the development of ICC.

Methods: The Cancer Genome Atlas (TCGA) provided the expression profiles of KMT2A in CHOL, which were then validated with clinical ICC samples from the Human Protein Atlas (THPA). The biological function of KMT2A was evaluated using plate colony formation and CCK8 assays. A joint analysis of public data, CHIP-PCR, Western Blotting, and RT-qPCR was carried out to provide mechanistic insights.

Results: The expression levels of KMT2A were notably elevated in tumor samples compared to healthy samples. When KMT2A was overexpressed in ICC cells, cell proliferation was significantly enhanced, while its knockdown resulted in the opposite outcome. Furthermore, KMT2A elevated H3K4me3 in the JAK2 promoter region, thereby promoting JAK2 expression. It was found that activating JAK2/STAT3 could lessen the suppression of ICC proliferation caused by KMT2A knockdown.

Discussion: In this study, a series of experiments was conducted. First, through public databases, we discovered that KMT2A expression was significantly higher in intrahepatic cholangiocarcinoma than in normal tissue. Furthermore, KMT2A promoted the proliferation of ICC cells. Finally, our findings indicate that KMT2A exerts its function, at least in part, by activating the JAK2/STAT3 signaling pathway via enhanced H3K4 trimethylation and increased JAK2 transcription.

Conclusion: KMT2A was significantly upregulated in intrahepatic cholangiocarcinoma and elevated H3K4me3 levels at the JAK2 promoter, leading to higher JAK2 expression and activation of the JAK2/STAT3 pathway, which, in turn, stimulated ICC cell proliferation. This study offers novel insights into the potential of KMT2A as both a prognostic biomarker and therapeutic target for intrahepatic cholangiocarcinoma.