Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma

Abstract

Group 3 medulloblastoma (G3 MB) carries the worst prognosis of all MB subgroups. MYC oncoprotein is elevated in G3 MB tumors; however, the mechanisms that support MYC abundance remain unclear. Using metabolic and mechanistic profiling, we pinpoint a role for mitochondrial metabolism in regulating MYC. Complex-I inhibition decreases MYC abundance in G3 MB, attenuates the expression of MYC-downstream targets, induces differentiation, and prolongs male animal survival. Mechanistically, complex-I inhibition increases inactivating acetylation of antioxidant enzyme SOD2 at K68 and K122, triggering the accumulation of mitochondrial reactive oxygen species that promotes MYC oxidation and degradation in a mitochondrial pyruvate carrier (MPC)-dependent manner. MPC inhibition blocks the acetylation of SOD2 and oxidation of MYC, restoring MYC abundance and self-renewal capacity in G3 MB cells following complex-I inhibition. Identification of this MPC-SOD2 signaling axis reveals a role for metabolism in regulating MYC protein abundance that has clinical implications for treating G3 MB.

Complex II ambiguities—FADH2 in the electron transfer system

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Targeting Group 3 Medulloblastoma by the Anti-PRUNE-1 and Anti-LSD1/KDM1A Epigenetic Molecules

“…Phenformin, a mitochondrial complex 1 inhibitor, induced significant cell death in Gr3 MB cells [99]. Then, OXPHOS suppression by using complex-I inhibitors (Phenformin, Rotenone, and IACS-010759), impaired the cell number of HD-MB03 (MYC-amplified Gr3 MB cells) after 24 h of treatment [100]. In particular, IACS-010759 treatment promoted differentiation and suppressed the growth and stemness of Gr3 MB cells [100].…”

“…Then, OXPHOS suppression by using complex-I inhibitors (Phenformin, Rotenone, and IACS-010759), impaired the cell number of HD-MB03 (MYC-amplified Gr3 MB cells) after 24 h of treatment [100]. In particular, IACS-010759 treatment promoted differentiation and suppressed the growth and stemness of Gr3 MB cells [100]. Of note, the oral administration of IACS-010759 impaired tumor growth and prolonged survival in a pre-clinical orthotopic Gr3 MB xenograft model [100].…”

“…In particular, IACS-010759 treatment promoted differentiation and suppressed the growth and stemness of Gr3 MB cells [100]. Of note, the oral administration of IACS-010759 impaired tumor growth and prolonged survival in a pre-clinical orthotopic Gr3 MB xenograft model [100]. β-blockers were reported to be able to disrupt mitochondrial bioenergetics, increasing radiotherapy efficacy in MB [101].…”