In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3362-3362
Abstract:
Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homoeostasis in mammalian cells. The current understanding of PDC regulation involves serine phosphorylation of pyruvate dehydrogenase (PDH) by PDH kinase (PDHK), which inhibits PDH and subsequently PDC, whereas dephosphorylation of PDH by PDH phosphatase (PDP) activates PDC. Here we report that lysine acetylation of PDHA1 and PDP1 is induced by EGF-stimulation in human cells, and is common in diverse human cancer cells. We found that K321 acetylation inhibits PDHA1 by recruiting PDHK1 and K202 acetylation inhibits PDP1 by dissociating its substrate PDHA1, both of which are important for the metabolic switch to glycolysis in cancer cells and promote tumor growth. Moreover, we identified mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) as the upstream acetyltransferase of PDHA1 and PDP1 using a novel shRNA library that targets the majority of acetyltransferases in the human genome, and SIRT3 as the deacetylase. Knockdown of ACAT1 results in decreased cancer cell proliferation and tumor growth. Furthermore, we found that EGFR and other tyrosine kinases including FGFR1 that are frequently dysregulated in human cancers phosphorylate PDP1 at Y381, which dissociates SIRT3 and recruits ACAT1 to PDC. Our findings suggest a novel mechanism where lysine acetylation of PDHA1 and PDP occurs in both normal and cancer cells, and contributes to inhibitory regulation of PDC, providing complementary insight into the current understanding of PDHA1 regulation. We also demonstrate that hierarchical, distinct post-translational modifications crosstalk to regulate PDC by controlling its molecular composition. Moreover, our findings for the first time link a mitochondrial acetyltransferase, ACAT1, to the Warburg effect and tumor growth, suggesting that the ACAT1-PDP1-PDHA axis represents a promising anti-cancer target. Citation Format: Jun Fan, Ting-Lei Gu, Titus Boggon, Sumin Kang, Jing Chen. Tyr-phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate pyruvate dehydrogenase complex and promote the Warburg effect. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3362. doi:10.1158/1538-7445.AM2014-3362
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-3362
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
