Abstract 1054: SNAI1 regulates the hexosamine biosynthetic pathway to promote tumorigenesis and oncogene-induced senescence escape in lung cancer
Authors: Taparra Kekoa , Wang Hailun , Nugent Katriana , Malek Reem , Groves Jen , Yildirir Gokben , Simons Brian , Felsher Dean , Zachara Natasha , Tran Phuoc 
Published: July 2016

Abstract
Lung cancer is the deadliest and most common malignancy worldwide. Tumor invasion and metastasis influence the dismal 16% overall 5-year survival. Evidence suggests malignancies commandeer epithelial plasticity programs like the epithelial-mesenchymal transition (EMT) to promote tumorigenesis, tumor progression, and metastasis. Furthermore, EMT has recently been linked to alterations in cancer metabolism, which can engender adaptation to environmental stress while supporting the macromolecular demand of rapid proliferation. Thus it is important to better understand the emerging roles of EMT in regulating cancer metabolism. SNAI1 is a master EMT regulator and is aberrantly overexpressed in many cancers including lung cancer. To investigate the role of SNAI1 in tumorigenesis, we created a novel inducible autochthonous mouse model. Our model reveals SNAI1 overexpressing mutant Kras mice generate identifiable tumors twice as fast (median = 14 weeks) as mice overexpressing mutant Kras alone (median = 30 weeks). To identify possible mechanisms of SNAI1-accelerated tumorigenesis, we used mRNA expression profiling. We identified significantly altered gene signatures related to metabolic reprogramming. Specifically, SNAI1 upregulates the hexosamine biosynthetic pathway (HBP) in mutant Kras-driven mouse lung tumors. SNAI1 elevates protein and mRNA of the rate limiting step (GFPT2) and final step (UAP1) of this pathway. This SNAI1-driven promotion of the HBP was recapitulated in vitro using human non-small cell lung cancer (NSCLC) SNAI1 isogenic cell lines. NSCLC mRNA expression data from The Cancer Genome Atlas (TCGA) also showed SNAI1 expression in patient tumor samples correlate with a significant tendency towards co-expression with HBP genes (Fisher's exact test, p&lt;0.05). Functionally, the final metabolite generated by the HBP, UDP-GlcNAc, is an essential nucleotide sugar found in a plethora of N- and O-linked glycosylations, regulating protein stability and activity. Here we show SNAI1 promotes flux through the HBP to promote increased total levels of O-GlcNAcylated proteins in lung tumors in vivo. In so doing, modulation of the HBP and specific glycosylations may impact cell death and senescence, suggesting a novel targetable EMT-HBP axis. Numerous oncogenes, including c-Myc and SNAI1 itself, are known to be stabilized by O-GlcNAcylation. This link is becoming of increasing importance in cancer biology, as half of the body of literature on O-GlcNAcylation and cancer has been published in the past three years. Together, our data suggest heightened protein O-GlcNAcylation, mediated by SNAI1 and the HBP, serves as a novel means by which EMT contributes to mutant Kras-induced lung tumorigenesis and tumor progression.
Citation Format: Kekoa Taparra, Hailun Wang, Katriana Nugent, Reem Malek, Jen Groves, Gokben Yildirir, Brian Simons, Dean Felsher, Natasha Zachara, Phuoc Tran. SNAI1 regulates the hexosamine biosynthetic pathway to promote tumorigenesis and oncogene-induced senescence escape in lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1054.