Abstract A05: The mitochondrial RNA polymerase is an essential downstream effector of the MYC oncoprotein

Much of the metabolic reprogramming seen in cancer cells, known as the Warburg effect, is regulated by the MYC oncoprotein. Among MYC-regulated changes are: addiction to exogenous glutamine and increased transcription of the lactate dehydrogenase-A gene. MYC also regulates expression of the cad gene, which encodes three enzymes in the pyrimidine biosynthesis pathway, as well as other enzymes linked to nucleotide biosynthesis. Another MYC-regulated change is increased mitochondrial biogenesis and mitochondrial genome (mtDNA) content, despite a decrease in ATP generation via the mitochondrial electron transport chain (ETC). Via a screen designed to isolate MYC targets whose transcription is tightly correlated with malignant transformation, the mitochondrial RNA polymerase (POLRMT) gene was identified by our group. POLRMT levels are regulated by MYC in cells from many forms of human cancer, including those from various forms of leukemia, lymphoma, myeloma, melanoma, and epithelial tumors. POLRMT is a nuclear gene that encodes the single-chain polypeptide RNA polymerase responsible for all transcription in the mitochondria. We have demonstrated that MYC controls transcription of the mitochondrial genome via POLRMT. Genetic rescue experiments show that induction of POLRMT is necessary for MYC to cause increased mtDNA content. Remarkably, blocking induction of POLRMT by MYC causes a synthetic lethality whereby the cells undergo apoptosis. This has been accomplished using either RNA...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Myc and Metabolism - Metabolomics: Poster Presentations - Proffered Abstracts Source Type: research