Rejuvenating sirtuins: the rise of a new family of cancer drug targets

Abstract

Sirtuins are a family of NAD+-dependent enzymes that was proposed to control organismal life span about a decade ago. While such role of sirtuins is now debated, mounting evidence involves these enzymes in numerous physiological processes and disease conditions, including metabolism, nutritional behavior, circadian rhythm, but also inflammation and cancer. SIRT1, SIRT2, SIRT3, SIRT6, and SIRT7 have all been linked to carcinogenesis either as tumor suppressor or as cancer promoting proteins. Here, we review the biological rationale for the search of sirtuin inhibitors and activators for treating cancer and the experimental approaches to their identification.

Fig. (1)

X-ray structure of human SIRT3 in complex with ADPR bound to Acetyl-coenzyme A synthetase 2 peptide containing a thioacetyl lysine (PDB code 3GLT). Different domains of the protein are color-coded (red for the Rossman-fold domain, yellow for zinc-binding domain, green for the cofactor-binding loop. The molecular structure of substrate peptide (green) and cofactor (yellow) are reported. The surfaces of substrate-binding site (purple) and NAD+-binding site (light blue) are also highlighted. (The color version of the figure is available in the electronic copy of the article).

Fig. (2)

Sirtuin inhibitors.

Fig. (3)

Sirtuins activators.