Cancer cells depend on altered nutrient uptake and metabolism to grow and divide. In order to appropriately regulate energy-intensive processes such as growth and proliferation, cells must be able to gauge their metabolic resources. My lab is interested in understanding how cells sense nutrient availability and integrate this information with signaling and transcriptional networks in order to modulate activities such as growth, proliferation, and differentiation. Current research focuses on elucidating the roles of nutrient-sensitive protein modifications in regulating signaling and gene expression in the contexts of cancer and metabolic disease.
Growth factor signaling directs nutrient uptake and metabolism, and reciprocally, intracellular metabolite levels influence signaling and gene expression. Many critical signaling molecules and transcription factors are subject to modifications, such as acetylation and glycosylation, that are metabolically sensitive and may be altered in cancer cells.
We have recently demonstrated that acetylation of histones, and associated changes in gene expression, are responsive to glucose availability in a manner dependent on ATP-citrate lyase (ACL), a metabolic enzyme that cleaves mitochondria-derived citrate to produce acetyl-CoA in the nucleus and cytoplasm. Hence, histones can be modified in a manner responsive to nutrient availability, potentially influencing multiple chromatin-dependent processes. A major current focus of the lab is to elucidate the mechanisms through which ACL regulates acetylation and its impact on signaling and gene expression, using cancer and metabolic cell types and mouse models.
A second area of interest is in understanding the role of the hexosamine biosynthetic pathway in regulating metabolism and growth. The hexosamine pathway is a branch of glucose metabolism that produces UDP-N-acetylglucosamine (UDP-GlcNAc), a donor substrate used in the production of several types of glycans, including N-linked glycans. Many cell surface and secreted proteins are modified co-translationally by N-linked glycosylation, and these glycoproteins can be influenced by metabolic state through glucose flux into the hexosamine pathway. Changes in the function and surface expression of glycoproteins can impact tumor growth by altering cancer cells’ interactions with their environment, including their ability to respond to growth factors and acquire nutrients. We are currently investigating how the hexosamine biosynthetic pathway is regulated in cancer cells and its impact on cancer cell growth and proliferation.
01. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005 May;115(5):1111-9. Review. PMID: 15864338.
02. Wellen KE, Fucho R, Gregor MF, Furuhashi M, Morgan C, Lindstad T, Vaillancourt E, Gorgun CZ, Saatcioglu F, Hotamisligil GS Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis. Cell. 2007 May 4;129(3):537-48. PMID: 17482547.
03. Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 2009 May 22;324(5930):1076-80. PMID: 19461003.
04. Wellen KE, Thompson CB. Cellular metabolic stress: considering how cells respond to nutrient excess. Mol Cell. 2010 Oct 22;40(2):323-32. Review. PMID: 20965425.
05. Wellen KE, Lu C, Mancuso A, Lemons JM, Ryczko M, Dennis JW, Rabinowitz JD, Coller HA, Thompson CB. The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev. 2010 Dec 15;24(24):2784-99. PMID: 21106670.
06. Lu C, Ward, PS, Kapoor, GS, Rohle, D, Turcan S, Abdel-Wahab, O, Edwards, CR, Khanin R, Figueroa, ME, Melnick A, Wellen KE, O’Rourke DM, Berger, SL, Chan, TA, Levine RL, Mellinghoff IK, and Thompson CB. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature; 2012 Feb 15. doi: 10.1038/nature10860.
07. Daye D and Wellen KE. Metabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol; 2012 Feb 11.
08. Jiang P, Du W, Mancuso A, Wellen KE, Yang X. Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature, published online. 2013. doi:10.1038/nature11776
09. Lee JV, Shah SA, and Wellen KE. Obesity, cancer, and acetyl-CoA metabolism. Drug Discovery Today: Disease Mechanisms, 2013 June; 10(1-2): e55-e61.
10. Londono Gentile T, Lu C, Lodato, PM, Tse S, Olejniczak S, Witze, ES, Thompson CB, and Wellen KE. DNMT1 is regulated by ATP-citrate lyase and maintains methylation patterns during adipocyte differentiation. Mol Cell Biol, 2013 July 29 [Epub ahead of print]
Alessandro Carrer - Postdoctoral Researcher
Caroline Kitzmiller - Administrative Coordinator
Ellen Jackson - Research Specialist
Joyce Lee - Graduate Student
Peter Lodato - Research Specialist
Ryan Powers - Undergraduate Researcher
Sarah Tse - Undergraduate Researcher
Sharanya Sivanand - Graduate Student
Supriya Shah - Postdoctoral Researcher
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