PL02.1.A DELINEATING AND TARGETING A NOVEL METABOLISM-BASED POST-TRANSLATIONAL MECHANISM REGULATING THE ABUNDANCE OF THE ‘UNDRUGGABLE’ ONCOPROTEIN C-MYC IN MEDULLOBLASTOMA
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AbstractBACKGROUNDBrain tumors are the leading cause of cancer death in children, and medulloblastoma (MB) is one of the most common pediatric central nervous system malignancies. Amplification of the c-MYC oncogene is frequently observed in the most aggressive and lethal subgroup of this disease, group 3 (G3), but not in other subgroups. Patients that have G3 MB tumors with high c-MYC abundance are more likely to present as metastatic and are prone to develop fatal recurrent tumors. Unfortunately, the functional ubiquity and disordered structure of c-MYC makes it difficult to target for cancer treatment. Therefore, it is critical to identify novel, out-of-the-box strategies to suppress oncogenic c-MYC in highly aggressive G3 MB brain tumors. Recently, metabolism has emerged as a major regulator of overall cellular signaling processes through post-translational and epigenetic mechanisms. While c-MYC is known to regulate cellular metabolism, whether metabolism plays a role in reciprocally supporting enhanced c-MYC abundance in cancer is unknown. We hypothesize that an intrinsic feedback mechanism may exist where metabolic activity modulates c-MYC abundance that could be exploited as a therapeutic strategy to improve outcomes for G3 MB patients.MATERIAL AND METHODSUsing various well-characterized G3 MB cells, patient-derived G3 MB cells, orthotopic intracerebellar xenograft models, patient tumor bioinformatics, detailed biochemical characterization, and point-mutation analyses, we have identified a novel metabolism-dependent post-translational modification that regulates c-MYC stability in G3 MB.RESULTSIn-depth molecular analyses unveiled that c-MYC is susceptible to oxidation and proteasomal degradation under conditions of metabolic stress. Targeting mitochondrial respiration via inhibition of complex-I promotes the accumulation of reactive oxygen species (ROS) and leads to rapid cysteine oxidation and proteasomal degradation of c-MYC in G3 MB cells, but not normal human brain astrocytes or neural stem cells (NSCs). Point mutation analysis combined with biochemical oxidation assays identified the specific cysteine residues of c-MYC that are susceptible to oxidation and ultimately responsible for enhanced c-MYC degradation following complex-I inhibition. Importantly, oral administration of a blood-brain barrier permeable complex-I inhibitor impaired the growth of intracerebellar MB xenograft tumors in mice, significantly prolonging animal survival.CONCLUSIONAltogether, these findings unveil a novel mechanism through which metabolism regulates the post-translational stability of c-MYC and provides insights for designing rationale therapeutic strategies for the treatment of MB patients.SUPPORTThis work is supported by a project grant from the Canadian Institutes of Health Research (CIHR).
