Janus-faced role of SIRT1

from NCBI

SIRT1, a NAD+-dependent histone/protein deacetylase, has been emerging as a crucial regulator of assorted physiological events through deacetylation of various proteins related to apoptosis, DNA repair, and metabolism. SIRT1 is also involved in tumorigenesis; but it is still under much debate whether SIRT1 stimulates or suppresses carcinogenic processes. SIRT1 inhibits inflammation and activities of transcription factors that exacerbate carcinogenesis. Moreover, SIRT1 contributes to preservation of genomic stability. Thus, SIRT1 takes part in prevention, retardation, and suppression of carcinogenesis. SIRT1 is supposed to be underexpressed in tumors if it is indeed a tumor suppressor. Contrary to this supposition, substantial proportions of human cancer specimens have shown overexpression of SIRT1. SIRT1 aggravates inflammation, inactivates tumor suppressors, and, concomitantly, activates protooncogenes. In addition, SIRT1 promotes cancer cell proliferation, invasion, migration, and chemoresistance, conferring survival advantages to cancer cells.

The subcellular localization of SIRT1 might be responsible, at least in part, for determination of its dual roles in tumorigenesis. However, there should be factors other than subcellular localization that modulate SIRT1 functions. For instance, the complex regulators of the SIRT1 activity, such as AROS and DBC1, should be considered. Moreover, SIRT1 deacetylation of c-Myc was found to modulate the stability of this oncoprotein in both positive and negative manners. In this case, the different subcellular localization of SIRT1 was insufficient to assign to it reciprocal regulation of c-Myc protein stability. Although the subcellular locailization of SIRT1 is not a sole determinant of functions of this deacetylase in tumorigenesis, it is evident that the nuclear and cytoplasmic SIRT1 might exert distinct functions. Cytoplasmic SIRT1 promoted neurite outgrowth in PC12 cells, which was inhibited by the nuclear SIRT1. Furthermore, a SIRT1 NLS mutant unable to enter the nucleus failed to suppress colony formation, whereas SIRT1-overexpressing cells showed a strong inhibitory effect.

In conclusion, SIRT1 might modulate tumorigenesis in both positive and negative manners, partially depending on its subcellular localization. However, further investigation is required to fully clarify whether subcellular localization of SIRT1 is indeed a fate-determinant of its oncogenic versus tumor-suppressing functions. In particular, it is important to determine whether the SIRT1 NLS and/or NES contain point mutation(s) in human cancer tissues. In addition, SIRT1 mutations within the NLS and/or NES domain(s) would be useful tools for better elucidating the specific functions of nuclear and cytoplasmic SIRT1.