BIMG-10. IDH1 MUTATIONS INDUCE ORGANELLE DEFECTS VIA DYSREGULATED PHOSPHOLIPIDS

Abstract

BACKGROUNDMetabolic alterations of lipids have been identified as a hallmark of neoplasms, with the most prevalent being the balance between saturated fatty acid (SFA) and monosaturated fatty acid (MUFA). Stearoyl-CoA desaturase1 (SCD1), converting SFA to MUFA, is increased in many cancers, leading to worse prognosis. In glioma, the role of SCD1 remains unknown. Isocitrate dehydrogenase (IDH) mutations have been most commonly observed in glioma, but the involvement of mutant IDH in SCD1 expression also remains unknown.METHODSWe conducted metabolic analysis to examine the alteration of SCD1 expression in genetically engineered glioma cell lines and normal human astrocyte (NHA). Lipid metabolic analysis was conducted by using LC-MS, Raman Imaging Microscopy and SCD1 expression was examined by Western-blotting and RT-PCR method. Electron microscopy was employed for organelle structure and genetic knock-down of SCD1 gene was performed.RESULTHerein, we uncovered increased MUFA and their phospholipids in Endoplasmic Reticulum (ER), generated by IDH1 mutation, that were responsible for Golgi and ER dilation. RNA seq data from The Cancer Genome Atlas, showed that SCD1 expression was significantly higher in IDH mutant gliomas compared with wild-type, and high SCD1 expression was associated with longer survival. Inhibition of IDH1 mutation or SCD1 silencing restored ER and Golgi morphology, while D-2HG and oleic acid induced morphological defects in these organelles. Moreover, addition of oleic acid, which tilts the balance towards elevated levels of MUFA, produced IDH1 mutant-specific cellular apoptosis.CONCLUSIONCollectively, our results suggest that IDH1 mutant-induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing a new insight on the link between lipids metabolism and organelle morphology in these cells, with potential and unique therapeutic implications. The results of the present study may also provide novel insights into the discovery of metabolic biomarkers for IDH mutant gliomas.