Sirtuins (SIRT1-7), the mammalian homologues of the silent information regulator 2 (Sir2) in yeast, are members of nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylase family proteins (8-10). Sirtuins have a critical role in genome stability, longevity, metabolism

SIRT2, one of nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylase family proteins, has been found to be involved in the proliferation and survival of acute myeloid leukemia (AML) cells. However, its effect on drug resistance on chemoresistant AML cells is unclear. In the present study, we first found that SIRT2 was expressed at higher level in the relapsed AML patients than the newly diagnosed patients. Consistent with this observation, the expression level of SIRT2 was higher in HL60/A cells than that in HL60 cells. Depletion of SIRT2 by shRNAs in HL60/A cells resulted in decreased MRP1 level, enhanced drug accumulation and triggered more apoptosis. By contrast, overexpression of SIRT2 in HL60 cells led to increased MRP1 level, drug efflux and attenuated drug sensitivity. Moreover, the decreased expression of phosphorylated ERK1/2 was detected in SIRT2-depleted HL60/A cells and increased expression of phosphorylated ERK1/2 was observed in SIRT2 overexpressed HL60 cells. Furthermore, blockage of ERK1/2 signaling pathway with the chemical inhibitor PD98059, further induced apoptosis of HL60/A cells conferred by SIRT2 depletion. Importantly, ERK1/2 inhibition was able to reverse the drug resistance of HL60 conferred by SIRT2 overexpression. Thus, our findings collectively suggested that the expression level of SIRT2 has a positive relationship with DNR/Ara-C resistance and activity of ERK1/2 signaling pathway. SIRT2 might regulate DNR/Ara-C sensitivity in AML cells at least partially through the ERK1/2 pathway. Introduction Acute myeloid leukemia (AML) is a genetically heterogeneous disorder, characterized by uncontrolled clonal proliferation of immature myeloid cells in the bone marrow and blood with concurrent depletion of effective hematopoiesis (1,2). The standard treatment of AML with cytotoxic chemotherapy has remained mostly unchanged over the past few decades, with dismal clinical outcome (3). One of the key issues of this poor result is the development of resistance to chemotherapeutic agents, which can lead to clinical relapse (4). Hence, novel antileukemia agents, especially for relapsed leukemias resistant to existing chemotherapeutic drugs are needed. Multidrug resistance (MDR) is a major problem in the treatment of various human hematological malignancies. Overexpression of the drug transporter P-glycoprotein (P-gp) and/or multidrug resistance-associated protein (MRP1) has generally been reported to correlate with prognosis in AML (5,6). MRP1, like P-gp belongs to the ATP binding cassette (ABC) superfamily of membrane transport protein (6). The difference between them is that the 190-kDa MRP1 can be localized on both the plasma and intracytoplasmic membranes, which can cause intracellular or cytoplasmic sequestration of the drug (5). MRP1 overexpression leads to the failure of numerous chemotherapy protocols when there is without P-gp overexpression, such as in HL60/A cells (7). Sirtuins (SIRT1-7), the mammalian homologues of the silent information regulator 2 (Sir2) in yeast, are members of nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylase family proteins (8-10). Sirtuins have a critical role in genome stability, longevity, metabolism and aging (9,10). Among them, SIRT1 is the direct homologue of the yeast Sir2 and has a wide range of cellular functions (11). Previous studies have suggested that SIRT1 has oncogenic ability in hematological malignancies, such as CLL, AML and even can be seen as a therapeutic target for CML and AML treatment to overcome resistance (12-14). Little is known about SIRT2, which is the primary cytoplasmic Sirtuin but shuttles continuously between the cytoplasmic and nuclear compartments during interphase and thus, it has been reported to participate in cell cycle progression, cell differentiation, and oxidative stress by modifing other proteins and regulating gene expression (15-17,24,29). SIRT2 has been SIRT2 mediates multidrug resistance in acute myelogenous leukemia cells via ERK1/2 signaling pathway HUA XU, YUANYE LI, LONG CHEN, CHIJUAN WANG, QI WANG, HAIRUI ZHANG, YANI LIN, QINGHUA LI and TIANXIANG PANG State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P.R. China Received July 25, 2015; Accepted September 4, 2015 DOI: 10.3892/ijo.2015.3275 Correspondence to: Professor Tianxiang Pang, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing Road 288, Tianjin 300020, P.R. China E-mail: [email protected]