Abstract
Histone H3 (H3K4) demethylase JARID1B is aberrantly upregulated in many types of tumor and has been proposed to function as oncogene. Here we show that JARID1B is elevated in moderate and high-differentiated human hypopharyngeal squamous cell carcinoma (HPSCC) compared with low-differentiated HPSCC. Overexpression of JARID1B in FaDu cells increased epithelial differentiation marker K10 expression and inhibited cell proliferation. JARID1B and K10 mRNA expression is high correlated in HPSCC patients. Mechanistically, we found JARID1B directly bound to PI3K/AKT signaling inhibitor SHIP1 gene promoter and decreased SHIP1 gene expression. Activation of downstream AKT resulted in increased β-catenin signaling, by which promoted target genes Fra-1 and Jun, together with other AP-1 transcription factors, leading to K10 expression. Forced expression of SHIP1 rescued JARID1B-induced phenotypes on FaDu cell differentiation and proliferation. Taken together, our findings provide first evidence that elevated expression of JARID1B has a critical role in promoting HPSCC differentiation and inhibiting proliferation, suggesting JARID1B may function as a tumor suppressor in squamous cell cancers and implying a novel important therapeutic strategy of HPSCC.
Highlights
Hypopharyngeal squamous cell carcinomas (HPSCC) have the worst survival though it only represents 3–4% of all head and neck cancers.[1]
We found that Jarid1b was high expressed in the moderate and high-differentiated HPSCC compared with the low-grade samples (Figure 1a)
To assess the potential role of Jarid1b in the regulation of HPSCC differentiation, Flag-Jarid1b was overexpressed in FaDu cells, which came from a hypopharyngeal squamous cell carcinoma
Summary
Hypopharyngeal squamous cell carcinomas (HPSCC) have the worst survival though it only represents 3–4% of all head and neck cancers.[1]. HPSCC can be treated by surgery on the early stage, whereas a large part of patients was found to have late-stage cancer at diagnosis.[5] In recent years, instead of surgical excision non-surgical treatments have been used to largely preserve organ function. Recent decades the growing understanding of molecular mechanisms involved in the cancer cell proliferation, differentiation and cell death has led to the development of multiple targeted therapies with significant clinical benefits. Jaird1b has been reported to be overexpressed in breast cancer,[7,8,9] lung cancer, bladder cancer,[10,11] colorectal cancer,[12] prostate cancer[13] and malignant melanoma.[14] Jarid1b is upregulated in these cancers and required for cancer cell proliferation and tumor growth. Β-catenin was phrosphorlated by AKT and the β-catenin target genes Fra-1 and Jun, together with other AP-1 genes, induced K10
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