Haploinsufficiency of SIRT1 Enhances Glutamine Metabolism and Promotes Cancer Development.
SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, plays a vital role in the regulation of metabolism, stress responses, and genome stability. However, the role of SIRT1 in the multi-step process leading to transformation and/or tumorigenesis, as either a tumor suppressor or tumor promoter, is complex and may be dependent upon the context in which SIRT1 activity is altered, and the role of SIRT1 in tumor metabolism is unknown. Here, we demonstrate that SIRT1 dose-dependently regulates cellular glutamine metabolism and apoptosis, which in turn differentially impact cell proliferation and cancer development. Heterozygous deletion of Sirt1 induces c-Myc expression, enhancing glutamine metabolism and subsequent proliferation, autophagy, stress resistance, and cancer formation. In contrast, homozygous deletion of Sirt1 triggers cellular apoptotic pathways, increases cell death, diminishes autophagy, and reduces cancer formation. Consistent with the observed dose dependence in cells, intestine-specific Sirt1 heterozygous mice have enhanced intestinal tumor formation, whereas intestine-specific Sirt1 homozygous knockout mice have reduced development of colon cancer. Furthermore, SIRT1 reduction, but not deletion, is associated with human colorectal tumors, and colorectal cancer patients with low protein expression of SIRT1 have a poor prognosis. Taken together, our findings indicate that the dose-dependent regulation of tumor metabolism and possibly apoptosis by SIRT1 mechanistically contribute to the observed dual roles of SIRT1 in tumorigenesis. Our study highlights the importance of maintenance of a suitable SIRT1 dosage for metabolic and tissue homeostasis, which will have important implications in SIRT1-small-molecule-activator/inhibitor-based therapeutic strategies for cancers.
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Natalie S X
NSX
Ren
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Ming
M
Ji
Stem Cell Toxicology Group, National Toxicology Program, Research Triangle Park, NC 27709, USA.
Erik J
EJ
Tokar
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Evan L
EL
Busch
Integrative Bioinformatics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Xiaojiang
X
Xu
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
DeAsia
D
Lewis
Department of Anaesthesia and Intensive Care, Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
Xiangchun
X
Li
Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Aiwen
A
Jin
Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Yanping
Y
Zhang
Department of Anaesthesia and Intensive Care, Institute of Digestive Disease and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
William K K
WKK
Wu
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Weichun
W
Huang
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Leping
L
Li
Integrative Bioinformatics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
David C
DC
Fargo
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Temitope O
TO
Keku
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Robert S
RS
Sandler
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. Electronic address: lix3@niehs.nih.gov.
Xiaoling
X
Li
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics*; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics*; D005973:Glutamine / Q000378:metabolism*; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism
D005973:Glutamine; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
SIRT1/Sirt1; autophagy; colon cancer; glutaminolysis; inflammation