T Malignant transformation is associated with numerous phenotypic alterations, some of which promote proliferation. Many of the signaling pathways involved in these changes ultimately converge upon the c- Myc (Myc) oncoprotein, a bHLH-ZIP transcription factor with hundreds of genetic targets. Indeed, primary de-regulation of Myc itself occurs in many cancers. The rapid growth and proliferation of Myc-transformed cells is associated with the up-regulation of anabolic pathways which supply the macromolecular precursors necessary to maintain these activities. It is currently believed that Myc alters metabolism by diverting glycolytic and TCA cycle intermediates into these anabolic pathways while concurrently increasing ATP synthetic rates to meet increased cellular energy demands. This may partly explain why many tumors display aerobic glycolysis (The Warburg Effect). We have recently shown that Myc is also needed to maintain the structure and function of mitochondrial electron transport chain (ETC) Complexes I and V, thus explaining why Myc-deficient cells are severely ATP-depleted. In extension of these findings, we have also observed that Myc regulates mitochondrial protein function at the post-translational level through its up-regulation of sirtuin 3 (Sirt3), the major mitochondrial protein deacetylase. Therefore, in Specifi Aim 1, we propose to determine how Sirt3 and Myc cooperatively regulate mitochondrial structure and function by determining how the major protein targets of Sirt3 are altered by Myc and acetylation. We also provide evidence that, in response to Myc inactivation and ATP depletion, the energy-sensing AMP-dependent protein kinase (AMPK) is activated to dampen energy-utilizing anabolic processes and restore ATP levels. Therefore, in Specific Aim 2, we will determine how Myc and AMPK communicate to balance metabolism and ATP levels. Finally, we provide evidence that Myc and the related Myc family member bHLH-ZIP protein, ChREBP, also communicate by coordinately regulating an as yet incompletely defined repertoire of glycolytic and lipogenic genes and that ChREBP expression as a pro-anabolic factor is inversely correlated with that of anti-anabolic AMPK. Therefore, Specific Aim 3 will characterize Myc's and ChREBP's cooperating roles in energy-generating processes particularly those related to glycolysis and lipogenesis. The overriding hypothesis of this application is that Myc communicates with and regulates energy sensing pathways, glycolysis, lipogenesis and the direct and post-translational control of mitochondrial function as a means of controlling cell proliferation. The proposed studies will utilize state-of-the-art methodologies and complementing in vitro and in vivo models. The three co-investigators possess strong and synergistic collaborative ties as well as specific areas of expertise in Myc biology (Prochownik), mitochondrial sirtuins and fatty acid metabolism (Goetzman), and glycolytic and lipogenic gene regulation (Scott).
The de-regulation of the Myc oncoprotein in cancer is associated with significant changes in metabolic control and energy utilization. In this application, we will investigate how three recently discovered Myc- regulated pathways, namely, those controlled by sirtuin 3, ChREBP and AMPK, sense changes in intracellular energy supplies and balance these with the high anabolic demands of the transformed cell.
|Goetzman, Eric S; Prochownik, Edward V (2018) The Role for Myc in Coordinating Glycolysis, Oxidative Phosphorylation, Glutaminolysis, and Fatty Acid Metabolism in Normal and Neoplastic Tissues. Front Endocrinol (Lausanne) 9:129|
|Dolezal, James M; Dash, Arie P; Prochownik, Edward V (2018) Diagnostic and prognostic implications of ribosomal protein transcript expression patterns in human cancers. BMC Cancer 18:275|
|Wang, Huabo; Dolezal, James M; Kulkarni, Sucheta et al. (2018) Myc and ChREBP transcription factors cooperatively regulate normal and neoplastic hepatocyte proliferation in mice. J Biol Chem 293:14740-14757|
|Zhu, Yahui; Gu, Li; Li, Yajun et al. (2017) miR-148a inhibits colitis and colitis-associated tumorigenesis in mice. Cell Death Differ 24:2199-2209|
|Dolezal, James M; Wang, Huabo; Kulkarni, Sucheta et al. (2017) Sequential adaptive changes in a c-Myc-driven model of hepatocellular carcinoma. J Biol Chem 292:10068-10086|
|Zhang, Yuxun; Bharathi, Sivakama S; Rardin, Matthew J et al. (2017) Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain. J Biol Chem 292:10239-10249|
|Ivanov, A A; Gonzalez-Pecchi, V; Khuri, L F et al. (2017) OncoPPi-informed discovery of mitogen-activated protein kinase kinase 3 as a novel binding partner of c-Myc. Oncogene 36:5852-5860|
|Kulkarni, Sucheta; Dolezal, James M; Wang, Huabo et al. (2017) Ribosomopathy-like properties of murine and human cancers. PLoS One 12:e0182705|
|Jackson, Laura E; Kulkarni, Sucheta; Wang, Huabo et al. (2017) Genetic Dissociation of Glycolysis and the TCA Cycle Affects Neither Normal nor Neoplastic Proliferation. Cancer Res 77:5795-5807|
|Cheng, Li; Zhu, Yahui; Han, Han et al. (2017) MicroRNA-148a deficiency promotes hepatic lipid metabolism and hepatocarcinogenesis in mice. Cell Death Dis 8:e2916|
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