Elevated expression of JMJD6 is associated with oral carcinogenesis and maintains cancer stemness properties.

Cancer stem cells (CSCs) are defined as a small subpopulation of cancer cells within a tumor and responsible for initiation and maintenance of tumor growth. Thus, understanding of molecular regulators of CSCs is of paramount importance for the development of effective cancer therapies. Here, we identified jumonji domain-containing protein 6 (JMJD6) as a novel molecular regulator of oral CSCs. JMJD6 is highly expressed in CSC-enriched populations of human oral squamous cell carcinoma (OSCC) cell lines. Moreover, immunohistochemical staining revealed significantly high level of JMJD6 in OSCC tissues compared to normal human oral epithelia, suggesting that expression of JMJD6 positively correlates with oral carcinogenesis. Subsequent functional analysis showed that knockdown of endogenous JMJD6 in OSCC strongly suppressed self-renewal capacity, a key characteristic of CSCs, and anchorage-independent growth. Conversely, ectopic expression of JMJD6 enhanced CSC characteristics including self-renewal, ALDH1 activity, migration/invasion and drug resistance. Expression of CSC-related genes was also markedly affected by modulating JMJD6 expression. Mechanistically, JMJD6 induces interleukin 4 (IL4) transcription by binding to its promoter region. IL4 rescues self-renewal capacity in JMJD6- knocked down OSCC cells, suggesting the importance of JMJD6-IL4 axis in oral CSCs. Our studies identify JMJD6 as a molecular determinant of CSC phenotype, suggesting that inhibition of JMJD6 may offer an effective therapeutic modality against oral cancer.