TMET-32. THE ROLE OF HOXC10 IN DRIVING GLIOBLASTOMA AGGRESSIVENESS

Abstract

Abstract BACKGROUND Glioblastoma (GBM) is an aggressive malignancy, with a tumor doubling time of just 49.6 days. Despite maximal safe surgical resection, radiation, and temozolomide, median survival is only 14.6 months. Homeobox gene, homeobox C10 (HOXC10), a transcription factor of the HOX10 family, is pivotal in neuronal development, upregulated in several cancers, including glioma, and correlates with poor survival. METHODS RNA sequencing analysis was done on our mouse glioma syngeneic cell lines. HOXC10 expression analysis was done on human and mouse GBM cell lines and tissues by immunoblotting and immunohistochemistry, respectively. HOXC10 and p16-/-silencing were done using 4 unique 29mer shRNA constructs in the GFP vector, respectively. Gene Ontology predicted HOXC10 functions. HOXC10 and pyrroline-5-carboxylic acid reductase 1 (PYCR 1), a proline biosynthetic enzyme co-expression was studied using immunofluorescence analysis. RESULTS HOXC10 is highly expressed in human and mouse GBM tissues. HOXC10 was upregulated only in the high-grade/aggressive cell line [EGFRvIII; p16-/- & GFAP Cre] and demonstrated increased expression with p16 deletion in the mouse glioma cell line. Compellingly, TCGA analysis of GBM correlated the negatively prognostic p16 homozygous deletion (HD) with HOXC10 upregulation. Gene Ontology supports the role of HOXC10 for proline biosynthesis and metabolism. Immunofluorescence on mouse GBM sections revealed co-expression of HOXC10 and PYCR1. HOXC10 silencing significantly decreased GBM cell line proliferation, induced apoptosis, and decreased PYCR1 expression in vitro. CONCLUSIONS HOXC10 expression is increased in GBM and with p16 HD. HOXC10 silencing significantly decreased GBM cell line proliferation and decreased PYCR1 expression. HOXC10-mediated proline biosynthesis may present a novel target to improve GBM survival.