WHSC1 Promotes Oncogenesis through Regulation of NIMA-Related Kinase-7 in Squamous Cell Carcinoma of the Head and Neck

Abstract

Squamous cell carcinoma of the head and neck (SCCHN) is a relatively common malignancy with suboptimal long-term prognosis, thus new treatment strategies are urgently needed. Over the last decade, histone methyltransferases (HMT) have been recognized as promising targets for cancer therapy, but their mechanism of action in most solid tumors, including SCCHN, remains to be elucidated. This study investigated the role of Wolf-Hirschhorn syndrome candidate 1 (WHSC1), an NSD family HMT, in SCCHN. Immunohistochemical analysis of locoregionally advanced SCCHN, dysplastic, and normal epithelial tissue specimens revealed that WHSC1 expression and dimethylation of histone H3 lysine 36 (H3K36me2) were significantly higher in SCCHN tissues than in normal epithelium. Both WHSC1 expression and H3K36me2 levels were significantly correlated with histologic grade. WHSC1 knockdown in multiple SCCHN cell lines resulted in significant growth suppression, induction of apoptosis, and delay of the cell-cycle progression. Immunoblot and immunocytochemical analyses in SCCHN cells demonstrated that WHSC1 induced H3K36me2 and H3K36me3. Microarray expression profile analysis revealed NIMA-related kinase-7 (NEK7) to be a downstream target gene of WHSC1, and chromatin immunoprecipitation (ChIP) assays showed that NEK7 was directly regulated by WHSC1 through H3K36me2. Furthermore, similar to WHSC1, NEK7 knockdown significantly reduced cell-cycle progression, indicating that NEK7 is a key player in the molecular pathway regulated by WHSC1.Implications: WHSC1 possesses oncogenic functions in SCCHN and represents a potential molecular target for the treatment of SCCHN. Mol Cancer Res; 13(2); 293-304. Ó2014 AACR.

AKT-mediated stabilization of histone methyltransferase WHSC1 promotes prostate cancer metastasis

“…The oncogenic role of WHSC1 was first reported in multiple myeloma, in which the (4;14)(p16;q32) translocation results in WHSC1 overexpression (29)(30)(31). WHSC1 is also frequently overexpressed in solid tumors such as oligodendroglioma, breast, prostate, and head and neck cancers (32)(33)(34). Cell culture studies indicated that WHSC1 modulates NIMA-related kinase-7 (NEK7), Twist family bHLH transcription factor 1 (TWIST1), and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κΒ) to promote tumorigenesis (34)(35)(36).…”

“…WHSC1 is also frequently overexpressed in solid tumors such as oligodendroglioma, breast, prostate, and head and neck cancers (32)(33)(34). Cell culture studies indicated that WHSC1 modulates NIMA-related kinase-7 (NEK7), Twist family bHLH transcription factor 1 (TWIST1), and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κΒ) to promote tumorigenesis (34)(35)(36). Nevertheless, the genetic characterization of WHSC1 to determine its role in PCa metastasis and the signaling coordinated by WHSC1 remain undefined.…”

WHSC1L1 drives cell cycle progression through transcriptional regulation of CDC6 and CDK2 in squamous cell carcinoma of the head and neck

“…Given that WHSC1L1 is recurrently amplified in SCCHN and that few studies have explored the role of PKMTs in SCCHN [8], we aimed to evaluate its potential function as an oncogenic force in this disease, and to elucidate relevant mechanisms of its oncogenic activity. In this study, we show that WHSC1L1 is significantly overexpressed in patients with SCCHN, its knockdown causes cell-cycle arrest and decrease in global H3K36 dimethylation levels, and that it promotes the coordinated transcription of a number of cell cycle genes, including CDK2 and CDC6, which are critical for the G1/S transition.…”

NSD2 contributes to oncogenic RAS-driven transcription in lung cancer cells through long-range epigenetic activation

“…Additionally, NSD2 has been reported to be upregulated in a number of solid cancers such as squamous cell carcinoma of the head and neck7, endometrial cancer8, lung cancer910, neuroblastoma11, bladder and colon cancer910, hepatocellular carcinoma12, ovarian carcinoma13 and prostate cancer14. Overexpression in solid tumors appears to occur in the absence of genetic alterations.…”