SIRT2: Controversy and multiple roles in disease and physiology

Sirtuin 2 (SIRT2) is an NAD+-dependent deacetylase that was under studied compared to other sirtuin family members. SIRT2 is the only sirtuin protein which is predominantly found in the cytoplasm but is also found in the mitochondria and in the nucleus. Recently, accumulating evidence has uncovered a growing number of substrates and additional detailed functions of SIRT2 in a wide range of biological processes, marking its crucial role. Here, we give a comprehensive profile of the crucial physiological functions of SIRT2 and its role in neurological diseases, cancers, and other diseases. This review summarizes the functions of SIRT2 in the nervous system, mitosis regulation, genome integrity, cell differentiation, cell homeostasis, aging, infection, inflammation, oxidative stress, and autophagy. SIRT2 inhibition rescues neurodegenerative disease symptoms and hence SIRT2 is a potential therapeutic target for neurodegenerative disease. SIRT2 is undoubtedly dysfunctional in cancers and plays a dual-faced role in different types of cancers, and although its mechanism is unresolved, SIRT2 remains a promising therapeutic target for certain cancers. In future, the continued rapid growth in SIRT2 research will help clarify its role in human health and disease, and promote the progress of this target in clinical practice.