Abstract #4352: The role of HOP tumor suppressor gene in head and neck cancer

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO Oral squamous cell carcinoma (OSCC) and nasopharyngeal carcinoma (NPC) are two distinct types of head and neck cancer (HNC) with very different etiologies; OSCC is caused primarily by tobacco and alcohol and NPC is strongly associated with Epstein Bar virus infection. HNC is a major world health problem and both OSCC and NPC are particularly prevalent in Asian countries. The identification of genes whose expression are de-regulated in both OSCC and NPC would be a significant advance because these genes are likely to be of fundamental importance to the development and progression of HNC in general. Using Affymetrix microarrays, we have compared gene expression in OSCC and NPC with that of the corresponding normal controls. The homeodomain-only protein, HOP, was found to be down-regulated in both tumor types and the results were validated in OSCC/NPC cell lines and tissue samples by RT-PCR and quantitative real-time PCR, respectively. The HOP gene contains two promoters that encode the identical protein via the expression of two transcripts, termed HOP\#945; and HOP\#946;. Treatment of OSCC cells with the DNA demethylating agent, Zebularine, together with the histone deacetylase inhibitor, TSA, restored HOP expression and pyrosequencing analysis of bisulphite treated DNA showed evidence of methylation within the CpG island of the HOP\#946; promoter, suggesting that HOP expression is down-regulated in part by epigenetic mechanisms. In cells where HOP was more readily detected, DNA sequence analysis showed that the coding sequence of HOP was wild type, indicating that HOP is unlikely to be inactivated by mutation. Transfection of HOP into an OSCC cell line resulted in a reduction in colony forming ability and those cells that stably expressed HOP grew significantly slower than vector-transfected controls and were more susceptible to UV-induced apoptosis. In summary, our data demonstrate that HOP functions as a tumor suppressor in OSCC and NPC and indicate that loss of HOP expression may be central to the pathogenesis of HNC by promoting cell proliferation and inhibiting mitochondrial-mediated apoptosis. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4352.