SIRT1, the most conserved NAD+-dependent protein deacetylase, is an important cellular metabolic and stress sensor. However, the role of this critical factor in cancer development remains unclear and inconclusive. SIRT1 has been shown to directly maintain genome stability and repress inflammation, thereby decreasing tumor growth. On the other hand, SIRT1 also has been reported to inhibit activities of tumor suppressors, promoting growth and survival of cancer cells. As a result, whether SIRT1 is an oncogene or tumor suppressor remains controversial.

We recently explored the possibility that SIRT1 regulates cancer development in a quantitative dose-dependent manner. We hypothesized that different SIRT1-regulated cellular pathways have distinct sensitivities to changes of SIRT1 dosages. These distinct sensitivities may differentiate the outcomes in cancer cell proliferation and growth, contributing to observed dual functions of SIRT1 in tumor development.

To test this hypothesis, we generated immortalized mouse embryonic fibroblasts (MEFs) and human colorectal cancer cell lines carrying two copies (WT), one copy (Het), or no copy (KO) of SIRT1 gene. Consistent with our hypothesis, SIRT1 Het cells displayed elevated proliferation in culture, increased colony formation on soft agar, and enhanced tumor formation in nude mice in a xenograft model, whereas SIRT1 KO cells exhibited reduced proliferation, colony formation, and cancer formation. Further mechanistic studies revealed that deletion of one copy of SIRT1 gene is sufficient to activate NF-κB and induce c-Myc expression, promoting cell proliferation, autophagy, and stress resistance in a glutamine-dependent manner. Deletion of both copies of SIRT1 gene, on the other hand, triggers cellular apoptotic pathways, leading to increased cell death, diminished autophagy, and reduced cancer formation. Consistently, intestine-specific SIRT1 heterozygous mice have enhanced intestinal tumor formation, whereas intestine-specific SIRT1 homozygous knockout mice have reduced development of colon cancer. Finally, expression levels of SIRT1 are reduced in human colorectal tumors, and reduced tumor SIRT1 expression correlates with poor prognosis in colorectal cancer patients.

In summary, our findings indicate that the dose-dependent regulation of tumor metabolism and possibly apoptosis by SIRT1 mechanistically contributes 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 activators/inhibitors based therapeutic strategies for cancers.