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, 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 129(3): 537-48, May 2007.
02. *Wellen KE, *Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB: ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324(5930): 1076-80, May 2009. Notes: *Both authors contributed equally to this work.
03. Wellen KE, Thompson CB: Cellular Metabolic Stress: Considering how cells respond to nutrient excess. Molecular Cell 40(2): 323-32, October 2010.
04. 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 & Development 24(24): 2784-99, December 2010.
05. Daye D, Wellen KE: Metabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis. Seminars in Cell & Developmental Biology 23(4): 362-9, June 2012.
06. Carrer A, Wellen KE: Metabolism and epigenetics: a link cancer cells exploit. Current opinion in biotechnology 34: 23-9, August 2015.
07. Lee JV, Shah SA, Wellen KE: Obesity, cancer, and acetyl-CoA metabolism. Drug Discovery Today: Disease Mechanisms 10(1-2): e55-e61, June 2013.
08. 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. Molecular and Cellular Biology 33(19): 3864-78, October 2013.
09. Lee JV, Carrer A, Shah S, Snyder NW, Wei S, Venneti S, Worth AJ, Yuan Z, Lim HW, Liu S, Jackson E, Aiello NM, Haas NB, Rebbeck TR, Judkins A, Won KJ Chodosh LA, Garcia BA, Stanger BZ, Feldman MD, Blair IA, Wellen KE: Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metabolism 20(2): 306-19, Aug 2014.
10. Shah S, Carriveau WJ, Li J, Campbell SL, Kopinski P, Lim HW, Daurio N, Trefely S, Won KJ, Wallace DC, Koumenis C, Mancuso A, Wellen KE: Targeting ACLY sensitizes castrate-resistant prostate cancer cells to AR antagonism by impinging on an ACLY-AMPK-AR feedback mechanism. Oncotarget Page: [Epub ahead of print] May 2016.
11. Zhao S, Torres AM, Henry R, Trefely T, Wallace M, Lee JV, Carrer A, Sengupta A, Kuo YM, Frey AJ, Meurs N, Viola JM, Blair IA, Weljie A, Snyder NW, Andrews AJ, Wellen KE: ATP-citrate lyase controls a glucose-to-acetate metabolic switch Cell Rep 17(4):1037-1052, 2016 Oct 18
12. Kinnaird A, Zhao S, Wellen KE*, Michelakis ED*: Metabolic regulation of epigenetics in cancer Nat Rev Cancer 16(11):694-707, 2016 Nov*co-corresponding authors
13. Carrer A, Parris JLD, Trefely S, Henry RA, Montgomery DC, Torres A, Viola JM, Kuo YM, Blair IA, Meier JL, Andrews AJ, Snyder NW, Wellen KE: Impact of high fat diet on tissue acyl-CoA and histone acetylation levels J Biol Chem, 2017 Jan 11. [Epub ahead of print].
Alessandro Carrer - Postdoctoral Researcher
AnnMarie Torres - Postdoctoral Researcher
John Viola - Research Specialist
Joyce Lee - Graduate Student
Karla Kim - Undergraduate Researcher
Lyndsey Makinen - Administrative Assistant
Sharanya Sivanand - Graduate Student
Sophie Trefely - Postdoctoral Researcher
Steven Zhao - Graduate Student
Sydney Campbell - Graduate Student
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