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. WHSC1 possesses oncogenic functions in SCCHN and represents a potential molecular target for the treatment of SCCHN.
Highlights
Over the last decade, epigenetic regulators have been implicated as key factors in many pathways relevant to cancer development and progression, such as cell-cycle regulation [1,2,3], invasiveness [4], signaling pathways [5], chemoresistance [6] and immune evasion [7]
Wolf–Hirschhorn syndrome candidate 1 (WHSC1) expression was significantly higher in SCCHN than in dysplastic and normal epithelium tissues (P < 0.0001; Mann–Whitney U test)
An inhibitor of EZH2, an histone methyltransferases (HMT), has already been introduced in phase I trials with the goal to target patients with refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma with the Y641 and A677 EZH2 activating mutations [45, 46]
Summary
Epigenetic regulators have been implicated as key factors in many pathways relevant to cancer development and progression, such as cell-cycle regulation [1,2,3], invasiveness [4], signaling pathways [5], chemoresistance [6] and immune evasion [7]. 9) have been identified, but their biologic functions are not fully characterized Because of their frequent overexpression and/or somatic mutations in a variety of cancer types, extensive efforts for the development of drugs targeting these enzymes have been initiated over the past several years [10, 11]. In this regard, an important group of HKMTs are the nuclear receptor Suppressor of variegation 3–9 Su(var), Enhancer of zeste and Trithorax (SET)-domain-containing (NSD) family members of HKMTs (NSD-HKMTs) NSD1, NSD2/WHSC1/MMSET, and NSD3/ WHSC1L1, which modulate the expression of genes through methylation of lysine 36 on histone H3 [12]. These HKMTs share 70% to 75% homology in their amino acid sequences and contain 4 basic domains which are conserved in other developmentassociated proteins: a Pro-Trp-Trp-Pro (PWWP) motif, which is a DNA methyl-lysine and methyl-arginine histone binder, a plant homeodomain PHD-type zinc finger (Cys3-His-Cys4) with methyl-lysine binding affinity, a high-mobility-group (HMG) box which has DNA-binding capacity, and a SET domain that possesses the methyltransferase activity [13]
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