Janus-faced role of SIRT1 in tumorigenesis

Abstract

Silent mating type information regulation 1 (Sirtuin 1; SIRT1) has been reported to regulate various physiological events, such as aging and metabolism, via deacetylation of histone and nonhistone proteins. Notably, cumulative evidence supports the notion that SIRT1 has a Janus-faced role in tumorigenesis. SIRT1 contributes to anti-inflammation, genomic stability, and cancer cell death, and hence it has tumor-suppressor properties. On the other hand, SIRT1 can stimulate oncogenic signaling pathways and can create a tumor microenvironment favorable to growth and survival of cancer cells. Such dual functions of SIRT1 may be determined, at least in part, by its subcellular localization. Interestingly, SIRT1 displays differential localization in normal cells and cancer cells, which in turn may affect the substrate specificity for its deacetylase activity.

Figure 1

The Janus face of SIRT1 in tumorigenesis. SIRT1 can inhibit inflammation and multistage carcinogenesis, acting as a tumor suppressor. Paradoxically, SIRT1 also accelerates tumorigenesis via multiple mechanisms, such as inactivation of tumor suppressors, activation of oncoproteins, and development of a microenvironment favorable for tumor survival.

Figure 2

Differential subcellular localization of SIRT1 in a human colon tumor specimen and normal colonic tissues. SIRT1 is highly expressed in human colon tumor tissues (B) compared with normal counterparts (A). Notably, SIRT1 showed cytoplasmic localization in colon tumors (B), whereas the adjacent normal tissues displayed rather nuclear-concentrated expression (A).

Figure 3

Some represantive intracellular proteins modulated by SIRT1. Nuclear and cytoplasmic SIRT1 may differentially target proteins as deacetylation substrates. Thus, SIRT1 may exert specific functions, depending on its subcellular localization.