Downregulated SIRT6 and upregulated NMNAT2 are associated with the presence, depth and stage of colorectal cancer

Abstract

Colorectal cancer (CRC) is an important cause of morbidity and mortality worldwide, and is difficult to detect in its early stages. Diagnostic and prognostic biomarkers are required, which may also be the basis for improving the targeted therapy for CRC. Sirtuin 6 (SIRT6) is a member of the sirtuin family of gene regulators, which have specific functions in genomic stability, gene transcription and energy metabolism in tumorigenesis. Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is a metabolic enzyme which can be deacetylated by sirtuins. In this study, tissue samples from 29 patients with histologically confirmed CRC of varying grade and stage were studied for SIRT6 and NMNAT2 expression by western blotting and reverse transcription-quantitative polymerase chain reaction. Immunohistochemistry was performed for SIRT6 and NMNAT2 expression in 113 paired (CRC and adjacent) tissue sections. SIRT6 protein and mRNA expression levels were significantly reduced in CRC tissues; NMNAT2 protein and mRNA expression levels were significantly increased in CRC tissues (P<0.01). A negative correlation between the expression of SIRT6 and NMNAT2 in CRC tissue samples was identified (r=−0.246, P<0.01). The reduced expression of SIRT6 and increased expression of NMNAT2 were associated with the tumor depth invasion, stage, differentiation grade (SIRT6 only) and the presence of lymph node metastasis (P<0.05). In conclusion, the findings of the present preliminary study demonstrated that the increased expression of NMNAT2 and reduced expression of SIRT6 may be associated with the progression of CRC. The downregulation of SIRT6 may promote the expression of NMNAT2. Further studies are indicated on the role of NMNAT2 and SIRT6 as potential diagnostic and prognostic biomarkers and as targets for therapy in CRC and other malignant tumors.

Subcellular compartmentalization of NAD+ and its role in cancer: A sereNADe of metabolic melodies

“…By contrast, the NMNAT2 gene appears to be amplified in most cancer types (source: www.cbioportal.org) (Cerami et al, 2012). Specifically, NMNAT2 upregulation in colorectal cancer correlates with the invasive depth and TNM stage (Cui et al, 2016;Qi et al, 2018). The upregulated NMNAT2 enzymatic activity in non-small cell lung cancer (NSCLC) can be triggered by SIRT3mediated deacetylation or p53 signaling (Pan et al, 2014).…”

Mitochondrial Deoxyguanosine Kinase Regulates NAD+ Biogenesis Independent of Mitochondria Complex I Activity

“…NMNAT family members catalyze the synthesis of NAD + both in the de novo pathway and the salvage pathway (10,11). Recent studies have shown that NMNAT2 is involved in colorectal cancer progression (12,13). NAPRT is involved in the synthesis of NAD + from nicotinic acid (9).…”

ROS-Mediated Apoptotic Cell Death of Human Colon Cancer LoVo Cells by Milk δ-Valerobetaine

“…In fact, downregulation of SIRT6 expression relates to poor prognosis in human colorectal, breast, ovarian, lung, and pancreatic tumors, whereas in other tumors poor outcomes are associated to its overexpression 15,17 . Downregulated SIRT6 and upregulated nicotinamide mononucleotide adenylyltransferase 2 are associated with the presence, depth invasion, stage, and differentiation grade of colorectal cancer (CRC) 18 . SIRT6 phosphorylation by PKCζ at threonine 294 residue mediates fatty acid β-oxidation 19 in human colon cancer cell lines, HCT116 and LoVo cells.…”