The Role of HDAC6 in Cancer

Histone deacetylase 6 (HDAC6), a member of the HDAC family whose major substrate is α-tubulin, has become a target for drug development to treat cancer due to its major contribution in oncogenic cell transformation. Overexpression of HDAC6 correlates with tumorigenesis and improved survival; therefore, HDAC6 may be used as a marker for prognosis. Previous work demonstrated that in multiple myeloma cells, inhibition of HDAC6 results in apoptosis. Furthermore, HDAC6 is required for the activation of heat-shock factor 1 (HSF1), an activator of heat-shock protein encoding genes (HSPs) and CYLD, a cylindromatosis tumor suppressor gene. HDAC6 contributes to cancer metastasis since its upregulation increases cell motility in breast cancer MCF-7 cells and its interaction with cortactin regulates motility. HDAC6 also affects transcription and translation by regulating the heat-shock protein 90 (Hsp90) and stress granules (SGs), respectively. This review will discuss the role of HDAC6 in the pathogenesis and treatment of cancer

Arsenic Trioxide Exerts Antimyeloma Effects by Inhibiting Activity in the Cytoplasmic Substrates of Histone Deacetylase 6

Arsenic trioxide (As2O3) has shown remarkable efficacy for the treatment of multiple myeloma (MM). Histone deacetylases (HDAC) play an important role in the control of gene expression, and their dysregulation has been linked to myeloma. Especially, HDAC6, a unique cytoplasmic member of class II, which mainly functions as α-tubulin deacetylase and Hsp90 deacetylase, has become a target for drug development to treat cancer due to its major contribution in oncogenic cell transformation. However, the mechanisms of action for As2O3 have not yet been defined. In this study, we investigated the effect of As2O3 on proliferation and apoptosis in human myeloma cell line and primary myeloma cells, and then we studied that As2O3 exerts antimyeloma effects by inhibiting activity in the α-tubulin and Hsp90 through western blot analysis and immunoprecipitation. We found that As2O3 acts directly on MM cells at relatively low concentrations of 0.5∼2.5 µM, which effects survival and apoptosis of MM cells. However, As2O3 inhibited HDAC activity at the relatively high concentration and dose-dependent manner (great than 4 µM). Subsequently, we found that As2O3 treatment in a dose- and time-dependent fashion markedly increased the level of acetylated α-tubulin and acetylated Hsp90, and inhibited the chaperone association with IKKα activities and increased degradation of IKKα. Importantly, the loss of IKKα-associated Hsp90 occurred prior to any detectable loss in the levels of IKKα, indicating a novel pathway by which As2O3 down-regulates HDAC6 to destabilize IKKα protein via Hsp90 chaperone function. Furthermore, we observed the effect of As2O3 on TNF-α-induced NF-κB signaling pathway was to significantly reduced phosphorylation of Ser-536 on NF-κB p65. Therefore, our studies provide an important insight into the molecular mechanism of anti-myeloma activity of As2O3 in HDAC6-Hsp90-IKKα-NFκB signaling axis and the rationale for As2O3 can be extended readily using all the HDAC associated diseases

Targeted Therapies for Acute Leukemia

Small molecules that can disrupt cell signaling by inhibiting protein-protein interactions hold promise for the development of therapeutics against leukemia. This study tested the effect of two compounds, XX-650-23 and tubacin, on cell survival and proliferation of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells, respectively. The cAMP response element-binding protein (CREB) is a nuclear transcription factor involved in cell proliferation, differentiation, and survival. Phosphorylated CREB recruits histone acetyltransferase, CREB-binding protein (CBP), and subsequent target gene expression occurs. The small molecule XX-650-23, identified through in silico screening methods, disrupts the CREB:CBP complex. We tested its effects on various AML cell lines using MTT and trypan blue exclusion assays. XX-650-23 preferentially targets AML cells, yielding 50 percent inhibitory concentrations (IC50s) ranging from 910 nM to 2.3 µM; we found that it synergizes with cytarabine. XX-650-23 delays the cell cycle in the G1/S phase and downregulates CREB target genes, such as cyclins A and D. Our results suggest that XX-650-23 delays the cell cycle, which stresses the cell, activating caspases involved in apoptosis, as indicated by PARP cleavage of HL60 cells.Histone deacetylase 6 (HDAC6), which deacetylates α-tubulin, has become a target for developing drugs to treat cancer. Previous studies demonstrated that inhibition of HDAC6 in multiple myeloma (MM) cells results in apoptosis. The small molecule tubacin (a tubulin acetylation inducer) inhibits HDAC6. We observed a higher antiproliferative effect of tubacin in ALL cells than in normal hematopoietic cells. Treatment with tubacin suppresses proliferation in ALL cells, with IC50s ranging from 1.2 µM to 2 µM. We found that it increased acetylation of α-tubulin within 30 minutes of treatment. Our study revealed that tubacin alone inhibits the aggresome pathway, resulting in an accumulation of polyubiquitinated proteins and apoptosis. Furthermore, unlike in MMs, it activated signaling pathways that do not involve JNK/SAP. We demonstrated that it indirectly inhibits the Na+/K+-ATPase pump, yielding lower K+ and higher Ca+ concentrations in the cytosol. Our results suggest that targeting CREB or HDAC6 alone or in combination with chemotherapy could provide a novel approach to treat AML and ALL, respectively