lncRNA regulation of glioblastoma progression and therapeutic resistance

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PROJECT SUMMARY Glioblastoma (GBM) is an incurable primary brain tumor that is characterized by regions of hypoxia and marked resistance to radiation. Glioma stem-like cells (GSCs) are a highly malignant subpopulation of cells that are highly resistant to standard cytotoxic treatments. GSCs have a high capacity for self-renewal and are frequently located in hypoxic areas, making them more even difficult to kill with radiation. GSCs therefore play an important role in disease recurrence. Long non-coding RNAs (lncRNAs) have recently been found to be dysregulated in cancer. LncRNAs have multiple functions including regulation of gene expression. We have found that the lncRNA Lucat1 is an important regulator of GSC response to hypoxia. Lucat1 is frequently overexpressed in GBM and is associated with poor prognosis in the aggressive IDH wt subtype. Our data support that Lucat1 is induced by hypoxia and forms a positive regulatory loop to promote HIF1a signaling. Functionally, our data support that Lucat1 helps to maintain GSCs in hypoxia and promote tumor growth. In this study, we propose to determine a mechanism by which Lucat1 regulates HIF1 signaling (Aim 1) and assess the function of Lucat1 in GSC maintenance and tumor progression (Aim 2). These studies will reveal a new and important mechanism by which hypoxic induction of Lucat1 drives GSC-mediated tumorigenesis. If successful, our findings will provide a new therapeutic approach for targeting GSCs in hypoxia to improve GBM control. This treatment strategy may be extended to other cancers including smoking-associated lung cancer and renal cell cancer that express high levels of Lucat1.