Tumour-suppressive function of SIRT4 in human colorectal cancer

Background:SIRT4, which is localised in the mitochondria, is one of the least characterised members of the sirtuin family of nicotinamide adenine dinucleotide-dependent enzymes that play key roles in multiple cellular processes such as metabolism, stress response and longevity. There are only a few studies that have characterised its function and assessed its clinical significance in human cancers.Methods:We established colorectal cancer cell lines (SW480, HCT116, and HT29) overexpressing SIRT4 and investigated their effects on proliferation, migration and invasion, as well as E-cadherin expression, that negatively regulates tumour invasion and metastases. The associations between SIRT4 expression in colorectal cancer specimens and clinicopathological features including prognosis were assessed by immunohistochemistry.Results:SIRT4 upregulated E-cadherin expression and suppressed proliferation, migration and invasion through inhibition of glutamine metabolism in colorectal cancer cells. Moreover, SIRT4 expression in colorectal cancer decreased with the progression of invasion and metastasis, and a low expression level of SIRT4 was correlated with a worse prognosis.Conclusions:SIRT4 has a tumour-suppressive function and may serve as a novel therapeutic target in colorectal cancer.

[1]  R. Deberardinis,et al.  The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. , 2008, Cell metabolism.

[2]  C. Dang,et al.  Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. , 2010, Cancer cell.

[3]  R. Poulsom,et al.  Level of expression of E-cadherin mRNA in colorectal cancer correlates with clinical outcome. , 1995, British Journal of Cancer.

[4]  S. Gygi,et al.  SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. , 2012, Molecular cell.

[5]  W. Che,et al.  SIRT4 Prevents Hypoxia-Induced Apoptosis in H9c2 Cardiomyoblast Cells , 2013, Cellular Physiology and Biochemistry.

[6]  F. Alt,et al.  SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic β Cells , 2006, Cell.

[7]  Xing Fu,et al.  Specific amino acid restriction inhibits attachment and spreading of human melanoma via modulation of the integrin/focal adhesion kinase pathway and actin cytoskeleton remodeling , 2005, Clinical & Experimental Metastasis.

[8]  Ying Yuan,et al.  Secreted Protein Acidic and Rich in Cysteines-like 1 Suppresses Aggressiveness and Predicts Better Survival in Colorectal Cancers , 2012, Clinical Cancer Research.

[9]  Lynette M. Smith,et al.  Activated KrasG12D is associated with invasion and metastasis of pancreatic cancer cells through inhibition of E-cadherin , 2011, British Journal of Cancer.

[10]  Gregory Stephanopoulos,et al.  The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4 , 2013, Cell.

[11]  C. Compton,et al.  AJCC Cancer Staging Manual , 2002, Springer New York.

[12]  T. Dønnem,et al.  The prognostic impact of NF-κB p105, vimentin, E-cadherin and Par6 expression in epithelial and stromal compartment in non-small-cell lung cancer , 2008, British Journal of Cancer.

[13]  Z. Yi,et al.  Positive Expression of LSD1 and Negative Expression of E-cadherin Correlate with Metastasis and Poor Prognosis of Colon Cancer , 2013, Digestive Diseases and Sciences.

[14]  Xiaoling Xu,et al.  SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. , 2013, Cancer cell.

[15]  S. Voelter-Mahlknecht,et al.  Fluorescence in situ hybridization and chromosomal organization of the sirtuin 4 gene (Sirt4) in the mouse. , 2009, Biochemical and biophysical research communications.

[16]  X. Zuo,et al.  Milk Fat Globule-Epidermal Growth Factor 8 Is Decreased in Intestinal Epithelium of Ulcerative Colitis Patients and Thereby Causes Increased Apoptosis and Impaired Wound Healing , 2012, Molecular medicine.

[17]  K. Mimori,et al.  Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial–mesenchymal transition , 2014, Proceedings of the National Academy of Sciences.

[18]  Liang Han,et al.  Indometacin ameliorates high glucose-induced proliferation and invasion via modulation of e-cadherin in pancreatic cancer cells. , 2013, Current medicinal chemistry.

[19]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[20]  Frank Speleman,et al.  miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis , 2010, Nature Cell Biology.

[21]  M. Welliver,et al.  The B55α subunit of PP2A drives a p53-dependent metabolic adaptation to glutamine deprivation. , 2013, Molecular cell.