Role of sirtuins in hepatocellular carcinoma progression and multidrug resistance: Mechanistical and pharmacological perspectives.

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer worldwide. Therapeutic strategies are still challenging due to the high relapse rate after surgery and multidrug resistance (MDR). It is essential to better understand the mechanisms for HCC progression and MDR for the development of new therapeutic strategies. Mammalian sirtuins (SIRTs), a family of seven members, are related to tumor progression, MDR and prognosis and were proposed as potential prognostic markers, as well as therapeutic targets for treating cancer. SIRT1 is the most studied member and is overexpressed in HCC, playing an oncogenic role and predicting poor prognosis. Several manuscripts describe the role of SIRTs2-7 in HCC; most of them report an oncogenic role for SIRT2 and -7 and a suppressive role for SIRT3 and -4. The scenario is more confusing for SIRT5 and -6, since information is contradictory and scarce. For SIRT1 many inhibitors are available and they seem to hold therapeutic promise in HCC. For the other members the development of specific modulators has just started. This review is aimed to describe the features of SIRTs1-7 in HCC, and the role they play in the onset and progression of the disease. Also, when possible, we will depict the information related to the SIRTs modulators that have been tested in HCC and their possible implication in MDR. With this, we hope to clarify the role of each member in HCC and to shed some light on the most successful strategies to overcome MDR.