Epigenetic reprogramming of autophagy leads to uncovering a novel therapeutic target for mutant IDH1 astrocytomas

Abstract

Mutant isocitrate dehydrogenase 1 (mIDH1) exhibits a gain of function mutation enabling 2-hydroxyglutarate (2HG) production and epigenetic reprogramming. This leads to enhanced DNA-damage response and radioresistance in mIDH1 gliomas. RNA-seq and ChIP-seq data revealed that human and mouse mIDH1 glioma neurospheres have downregulated gene ontologies (GOs) related to mitochondrial metabolism and upregulated GOs related to autophagy. Decreased mitochondrial metabolism was accompanied by decreased glycolysis, rendering autophagy a source of energy in mIDH1 gliomas. Human and mouse mutant IDH1 glioma cells exhibited increased expression of pULK1-S555 and enhanced LC3 I/II conversion, indicating augmented autophagy. Additionally, scRNA-seq data from human mIDH1 astrocytoma patients samples showed decreased mitochondrial metabolism and increased autophagy. We further demonstrate that inhibiting autophagy in vivo by systemic administration of synthetic protein nanoparticles encapsulating siRNA targeting Atg7 sensitized mIDH1 glioma cells to radiation-induced cell death, resulting in tumor regression, long-term survival, and immunological memory. In summary, our work uncovered that autophagy is a critical pathway for survival in mIDH1 gliomas and by blocking this pathway we can elicit radiosensitivity in vitro in human and mouse mIDH1 glioma cells, and in vivo in genetically engineered mouse models. Our data also highlights that blocking autophagy has significant potential for clinical translation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/584091v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@111f4a9org.highwire.dtl.DTLVardef@1d5bb30org.highwire.dtl.DTLVardef@f467ecorg.highwire.dtl.DTLVardef@1d2e9b5_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Our genetically engineered mIDH1 mouse glioma model harbors IDH1R132H in the context of ATRX and TP53 knockdown. The production of 2-HG elicited an epigenetic reprogramming associated with a disruption in mitochondrial activity and an enhancement of autophagy in mIDH1 glioma cells. Autophagy is a mechanism involved in cell homeostasis related with cell survival under energetic stress and DNA damage protection. Autophagy has been associated with radio resistance. The inhibition of autophagy thus radio sensitizes mIDH1 glioma cells and enhances survival of mIDH1 glioma-bearing mice, representing a novel therapeutic target for this glioma subtype with potential applicability in combined clinical strategies. C_FIG