The metabolic switch from oxidative phosphorylation to aerobic glycolysis in cancer/leukemia cell has been suggested to be due to, in part, attenuated mitochondrial function, which is suggested to be achieved through inhibition of pyruvate dehydrogenase complex (PDC). Pyruvate dehydrogenase A (PDHA) is the first and most important enzyme component of PDC, which converts pyruvate to acetyl-CoA that subsequently enters into the Krebs cycle. PDHA activity is negatively regulated by phosphorylation at several serine sites. Phosphorylation of PDHA by PDH kinase 1 (PDHK1) results in the inactivation of PDC, while dephosphorylation by PDH phosphatase 1 (PDP1) restores PDC activity. Although PDHK1 has been suggested to be upregulated by Myc and HIF-1?, how oncogenic signals inhibit PDC to regulate cancer cell metabolism still remains largely unknown. Interestingly, our proteomics studies revealed that in cancer cells, PDP1 and PDHA are inhibited by acetylation at K202 and K321, respectively. Moreover, we identified mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) as the upstream enzyme that acetylates and inhibits PDP1 and PDHA, and consequently PDC flux. Furthermore, we found that oncogenic FGFR1 phosphorylates and activates ACAT1. Stable knockdown of ACAT1 in cancer cells results in decreased glycolysis and increased OXPHOS, as well as reduced cancer cell proliferation and tumor growth. Thus, our hypothesis is that oncogenic TKs such as FGFR1 phosphorylate and activate mitochondrial ACAT1 to inhibit PDHA and PDP1 via lysine acetylation, which consequently attenuates PDC function to promote the Warburg effect and tumor growth. This represents a new concept that the transforming signals of oncogenic TKs could be mediated at least in part through regulation of lysine acetylation levels of key downstream effectors.
Three Specific Aims are proposed: (1) To determine whether FGFR1-dependent tyrosine phosphorylation of ACAT1 is important for ACAT1 activation and promotion of cancer metabolism and tumor growth; (2) To elucidate the molecular mechanisms by which ACAT1 binds to, acetylates and inhibits PDP1 and/or PDHA; (3) To examine whether ACAT1-dependent lysine acetylation of PDHA and PDP1 in cancer cells is sufficient to promote the Warburg effect and tumor growth.
The metabolic switch from oxidative phosphorylation to aerobic glycolysis in cancer/leukemia cell may be due to, in part, attenuated mitochondrial function, which is suggested to be achieved through inhibition of pyruvate dehydrogenase complex (PDC). However, how oncogenic signals regulate PDC components including pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1) to attenuate PDC activity in cancer metabolism remains largely unknown. Our hypothesis is that oncogenic TKs such as FGFR1 phosphorylate and activate mitochondrial acetyl-coA acetyltransferase 1 (ACAT1) to inhibit PDHA and PDP1 via lysine acetylation, which consequently attenuates PDC function to promote the Warburg effect and tumor growth.
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