The RNA-binding protein heterogenous ribonucleoprotein A18 (hnRNP A18) is a new protein translation regulator found to be elevated in many cancers. Previous work from our lab has shown that hnRNP A18 is able to bind and regulate the translation of a group of mRNAs under stress conditions, including hypoxia. Hypoxia has largely been recognized as an innate characteristic of solid tumors and plays numerous cellular and physiologic roles such as cell proliferation, invasion, migration, metastasis, and angiogenesis. Given its extensive function in solid tumors, combined with computational results showing a possible hnRNP A18 signature motif in the 3’UTR of HIF-1α, we sought to determine if hnRNP A18 binds HIF-1α mRNA and how this affects tumor promotion and growth. Results: Our data indicates that hnRNP A18 protein is able to bind HIF-1α mRNA. Under hypoxic conditions, down-regulation of hnRNP A18 significantly decreases HIF-1α mRNA stability, leading to reduced amounts of HIF-1α protein levels in melanoma cells. Treatment with CoCl2 increases hnRNP A18 protein levels in melanoma cells, but not in normal melanocytes. Additionally, colony survival assay demonstrates that down-regulation of hnRNP A18 decreases cells’ survival rates under a hypoxic environment. The functional significance of this effect was observed in a mouse xenograft model where down-regulation of hnRNP A18 significantly reduced melanoma and breast tumor growth. Immunohistochemistry staining of xenograft specimens showed overlapping localization of hnRNP A18 to the tumor hypoxic regions. Lastly, proteome profiling of the xenograft tumors showed a significant decrease of key angiogenic-related factors (e.g., angiogenin, endoglin, VEGF) when hnRNP A18 is reduced. Conclusion: Heterogenous ribonucleoprotein A18 is able to regulate HIF-1α mRNA and modulate its protein levels under hypoxic conditions. The oxygen-deprived regions generated in the central core of a solid tumor leads to up-regulation of hnRNP A18 and consequently HIF-1α, resulting in tumor growth and promotion. New therapeutics targeting hnRNP A18 would therefore be a logical next-step in developing a novel mechanism-based therapy for cancer treatment.
Citation Format: Elizabeth T. Chang, Palak Parekh, Qingyuan Yang, France Carrier. Regulation of HIF-1α by hnRNP A18 contributes to tumor promotion under hypoxic conditions. [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 2796.