SIRT2 finds a place in the family

Sirtuin 2 may suppress tumor formation in mice and humans

Sirtuins are a family of proteins that have been implicated in processes ranging from aging and tumor formation to obesity and cerebral ischemia. Seven sirtuin proteins are known to exist in mammals, two of which (SIRT1 and SIRT3), are known tumor suppressor genes. The function of sirtuin 2 (SIRT2) remained unclear however, until recent research from scientists at the National Institute of Health, Vanderbilt University and the University of Texas, Dallas discovered that SIRT2 could play an important role in preventing cancer. In a paper published in Cancer Cell this week, the researchers describe the role of SIRT2 in maintaining genomic stability in cells, a function critical in aging and cancer-related processes.

The scientists began their experiments by eliminating expression of the SIRT2 gene in mice. The absence of SIRT2 had no apparent effects on embryonic and early development in the mice, nor did their organs show any obvious abnormalities. However, cultured mouse embryonic fibroblast cells (MEFs) from the mutants grew more slowly than normal (wild-type) fibroblasts, and stopped growing earlier, implying that SIRT2 is important for cell proliferation. The mutant cells also had more errors in chromosome segregation during cell division: 35% of mutant cells had more or less chromosomes than normal (less than 5% of wild-type cells had similar defects).

Could these errors in cell division affect cancer risk? Observing the SIRT2 mice over a 2-year period, the researchers found that 60% of SIRT2 mutant mice developed some form of cancer by 24 months. Unusually, tumor formation in these mice showed a gender-specific pattern. Female mice developed breast cancers, whereas males developed tumors in multiple organs, including the lungs, pancreas, stomach and prostate.

Previous research has suggested that SIRT2, a histone deacetylase, is essential during mitosis and is associated with forming chromosomal structures for normal cell division. Exploring the molecular basis of this function through several experiments, this new research reveals interactions of SIRT2 with molecules critical to normal mitosis in cells, such as Aurora proteins and the anaphase promoting complex APC/C. Cells lacking SIRT2 end up with many abnormalities in cell division, including centrosome amplification, metaphase arrest and cell death during mitosis.

On chr. 19, the SIRT2 gene is located near the centromere

The authors also extend their experiments to human cancers, finding that breast and hepatic tumor samples expressed the SIRT2 protein at levels about 1.5 -2.5 times less than (corresponding) normal tissues. Examining existing data in Oncomine, they found similar trends in other human cancers, like renal carcinomas, glioblastoma and prostate carcinomas. Though there’s no obvious explanation for the gender-specificity of the tumors that mice developed, this research strongly supports further studies on SIRT2 function in cancers.

Exploring the SIRT2 gene in NextBio’s Disease Atlas, we found nearly 600 studies linking SIRT2 disruptions to several cancer types. We restricted our search to human studies of gene expression differences between diseased and normal tissues (currently 120 studies). We selected 23 biosets for meta-analysis, and found SIRT2 expression was altered at least 1.5 fold (relative to normal tissue) in all 23. Most primary cancers showed a decrease in SIRT2 expression consistent with the observations described in this study. However, we found that some neural tumors appear to show an increase, rather than decrease, in SIRT2 levels relative to normal tissues. The fold-change in SIRT2 expression also seems to be higher in metastatic breast tumors relative to primary tumors. Prostate cancer also shows a similar trend, with more advanced stages and metastatic tumors showing an increase in SIRT2 expression.

Fold-change in SIRT2 gene expression in cancer samples relative to normal tissues. *denotes average of at least 2 datasets, SD < 0.05

NextBio analysis of public genomic data supports the conclusions of this study with evidence from experiments on cell lines, tissues and a variety of clinical samples. Analysis of somatic mutations or differences in DNA methylation in the SIRT2 promoter region could offer further insight into the significance of SIRT2 to specific sub-types of human cancers.