Sorting out functions of sirtuins in cancer

Abstract

The sirtuins (SIRT 1-7) comprise a family of NAD⁺-dependent protein-modifying enzymes with activities in lysine deacetylation, adenosinediphospho(ADP)-ribosylation, and/or deacylation. These enzymes are involved in the cell's stress response systems and in regulating gene expression, DNA damage repair, metabolism and survival. Sirtuins have complex roles in both promoting and/or suppressing tumorigenesis. This review presents recent research progress concerning sirtuins and cancer. On one hand, functional loss of sirtuin genes, particularly SIRT1, involved in maintaining genome integrity and DNA repair will promote tumorigenesis because of genomic instability upon their loss. On the other hand, cancer cells tend to require sirtuins for these same processes to allow them to survive, proliferate, repair the otherwise catastrophic genomic events and evolve. The bifurcated roles of SIRT1, and perhaps several other sirtuins, in cancer may be in part a result of the nature of the genes that are involved in the cell's genome maintenance systems. The in-depth understanding of sirtuin functions may have significant implication in designing precise modulation of selective sirtuin members to aid cancer prevention or treatment under defined conditions.

Fig. 1

Comparison of mammalian sirtuins. The amino acid length of each mature main form of sirtuins is indicated at the end of each protein, with the conserved catalytic domain illustrated in grey. Principal enzymatic activities and primary cellular localization are shown.

Fig 2

Regulation of SIRT1 gene expression and activities in cancer cells SIRT1 transcription is activated by Myc, E2F1, or BCR-ABL in part through STAT5, but repressed by HIC1 and p53. The sites for transcriptional factor binding are shown. SIRT1 mRNA is stabilized by HuR but degraded by miR34a and miR200a. SIRT1 activity is enhanced by AROS but inhibited by DBC1.

Fig. 3

A model for bifurcated SIRT1 roles in cancer through genome maintenance SIRT1 promotes genome maintenance in both normal and cancer cells under genotoxic stress and DNA damage. Activation of DNA repair with high fidelity in normal cells improves genome stability and suppresses tumor formation. Activation of DNA repair with low fidelity in cancer cells prevents catastrophic genomic events and renders cancer cell survival, but allows cancer cells to accumulate non-fatal lesions and more mutations to evolve towards high grade malignancy and drug resistance under chemotherapy.