WHSC1L1 drives cell cycle progression through transcriptional regulation of CDC6 and CDK2 in squamous cell carcinoma of the head and neck
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Vassiliki Saloura1, Theodore Vougiouklakis1, Makda Zewde1, Kazuma Kiyotani1, Jae-Hyun Park1, Guimin Gao2, Theodore Karrison2, Mark Lingen3, Yusuke Nakamura1,4, Ryuji Hamamoto1
1Department of Medicine, University of Chicago, Chicago, IL, USA
2Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
3Department of Pathology, University of Chicago, Chicago, IL, USA
4Department of Surgery, University of Chicago, Chicago, IL, USA
Vassiliki Saloura, email: email@example.com
Keywords: WHSC1L1, squamous cell carcinoma of the head and neck, CDC6, CDK2, H3K36me2
Received: February 12, 2016 Accepted: May 15, 2016 Published: June 07, 2016
Wolf-Hisrchhorn Syndrome Candidate 1-Like 1 (WHSC1L1) is a protein lysine methyltransferase that is recurrently amplified (8p11.23) in patients with squamous cell carcinoma of the head and neck (SCCHN). In this study, we investigated the oncogenic role of WHSC1L1 in SCCHN. Using immunohistochemistry on tissue microarrays of patients with locoregionally advanced SCCHN, we found that WHSC1L1 is significantly overexpressed in patients with SCCHN, and is associated with poor grade and heavy smoking history. Knockdown of WHSC1L1 expression resulted in significant growth suppression and reduction of H3K36 dimethylation (H3K36me2) in SCCHN cells. Chromatin immunoprecipitation analysis showed that WHSC1L1 and H3K36me2 are enriched in the gene bodies of the cell cycle-related genes CDC6 and CDK2, implying that WHSC1L1 directly regulates the transcription of these genes. According to the importance of CDC6 and CDK2 for G1 to S transition, WHSC1L1 knockdown induced strong G0/G1 arrest which was rescued by introduction of wild-type WHSC1L1 but not by that of enzyme-inactive WHSC1L1. Our results imply that WHSC1L1 and its product H3K36me2 are essential for the transition from G1 to S phase in SCCHN cells and that WHSC1L1 could serve as a rational target for anticancer drug development for patients with head and neck cancer.
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