Poster abstracts

Poster number 28 submitted by Jessica Fleming

Testing Ahr and Hdac9 for a Role in Cutaneous Squamous Cell Carcinoma Susceptibility

Jessica L. Fleming (MVI-MG, OSU), Laura E. Skeeles (MVI-MG, OSU), Kimberly Mahler (MVI-MG, OSU), Jian-Hua Mao (Dermatology, UCSF), Allan Balmain (Dermatology, UCSF), Amanda Ewart Toland (MVI-MG, OSU)

Abstract:
Cutaneous squamous cell carcinoma (SCC) is one of the most common malignancies in the Western World, however little is known about the genetic risk factors. This project focuses on the identification of candidate genes for SCC risk. We identified a susceptibility locus, Skts5, on mouse chromosome 12 through F1 backcrosses between resistant Mus Spretus (Spret/GS) and susceptible Mus Musculus (NIH/Ola) mice. We define candidate genes as those containing sequence variations and/or differential gene expression between the two strains. We hypothesize that one or more of these genes play a role in SCC progression. In vitro studies were conducted using murine NIH-3T3 and SPRET fibroblast, normal keratinocyte (C5N), and SCC (A5, B9) cell lines. Ahr is a transcription factor that has been shown to play roles in tumor progression and suppression. We found that SPRET has lower total and active Ahr protein levels compared to NIH-3T3. Ahr is only active when in a complex with Arnt or RelB. We found that the Ahr/Arnt complex is more common in NIH-3T3 whereas the Ahr/RelB complex is more abundant in SPRET; thereby possibly contributing to their susceptibility and resistance respectively. Hdac9 is a class II histone deacetylase and plays a role in transcriptional regulation. We found that SPRET has a significantly higher protein level of Hdac9 than NIH-3T3. We found that SPRET has lower levels of Hdac9 downstream targets, Gli1 and FoxP3, than NIH-3T3. It is possible that the elevated Hdac9 levels in SPRET may contribute to its resistance by silencing key oncogenes. Future experiments include cloning each isoform of Ahr and Hdac9 and performing in vitro studies to assess their effects on growth rate, cell morphology, motility and migration, and expression of downstream targets. If the Skts5 locus contributes to the onset of cancer, we will be able to further investigate the functional roles of each gene in cells and move into human studies.

Keywords: SCC, Ahr, Hdac9