Histone demethylase JMJD6 enhances cancer stem cell phenotype in oral squamous cell carcinoma cells

摘要

Jumonji Domain Containing 6 (JMJD6) is a histone arginine demethylase that preferentially removes methyl groups from dimethylated arginine 2 of histone 3 (H3R2me2) and arginine 3 of histone 4 (H4R3me2), thereby enabling dynamic regulation of transcription. JMJD6 also regulates gene expression by modulating RNA splicing, suggesting that JMJD6 is a multifaceted epigenetic regulator. Clinically, JMJD6 overexpression is strongly linked to poor prognosis in various human cancers, including breast and lung. JMJD6 is also reported to promote cancer cell migration/invasion and angiogenic sprouting, two phenotypes of which are well known for cancer stem cell (CSCs; also known as cancer initiating cells) characteristics. JMJD6 is also known to be essential for the differentiation of multiple tissues and cells during embryogenesis. Recent studies revealed that histone methylation played a critical role in controlling stemness of normal stem cells. Although CSCs share molecular and phenotypic characteristics with normal stem cells, a considerable knowledge gap remains in our understanding of epigenetic regulation of oral CSCs particularly by histone demethylases.;To investigate potential involvement of histone demethylases in oral CSCs, we screened expression of 22 known histone demethylases in CSC-enriched oral squamous cell carcinoma (OSCC) populations. Among them, JMJD6 was unequivocally overexpressed in all tested CSC-enriched OSCC populations. Subsequent functional analysis showed that knockdown of endogenous JMJD6 in OSCC strongly suppressed CSC phenotypes (e.g., decreased self-renewal capacity and migration). Conversely, ectopic expression of JMJD6 enhanced the CSC phenotypes. Interestingly, expression of CSC-related genes (e.g., pluripotency transcription factors and cytokines) was markedly affected by modulating JMJD6 expression. We further found that JMJD6 regulates the expression of CSC-specific cytokines (i.e., IL-4, IL-5, MIP-1alpha, MIP-1beta, IFNalpha, and IFNbeta) by binding to their promoter regions. Our study suggests that JMJD6 promotes oral CSC phenotype by epigenetically regulating its target genes.