Histone deacetylase 3 as a novel therapeutic target in multiple myeloma.

Histone deacetylases (HDACs) represent novel molecular targets for the treatment of various types of cancers, including multiple myeloma (MM). Many HDAC inhibitors have already shown remarkable anti-tumor activities in the preclinical setting; however, their clinical utility is limited due to unfavorable toxicities associated with their broad range HDAC inhibitory effects. Isoform-selective HDAC inhibition may allow for MM cytotoxicity without attendant side effects. In this study, we demonstrated that HDAC3 knockdown and a small molecule HDAC3 inhibitor BG45 trigger significant MM cell growth inhibition via apoptosis, evidenced by caspase and PARP cleavage. Importantly, HDAC3 inhibition downregulates phosphorylation (tyrosine 705 and serine 727) of STAT3. Neither IL-6 nor bone marrow stromal cells overcome this inhibitory effect of HDAC3 inhibition on p-STAT3 and MM cell growth. Moreover, HDAC3 inhibition also triggers hyperacetylation of STAT3, suggesting crosstalk signaling between phosphorylation and acetylation of STAT3. Importantly, inhibition of HDAC3, but not HDAC1 or HDAC2, significantly enhances bortezomib-induced cytotoxicity. Finally, we confirm that BG45 alone and in combination with bortezomib trigger significant tumor growth inhibition in vivo in a murine xenograft model of human MM. Our results indicate that HDAC3 represents a promising therapeutic target, and validate a prototype novel HDAC3 inhibitor BG45 in MM.

组蛋白去乙酰化酶（HDACs）是治疗包括多发性骨髓瘤（MM）在内的多种癌症的新型分子靶点。许多HDAC抑制剂在临床前研究中已显示出显著的抗肿瘤活性；然而，由于其广泛的HDAC抑制作用相关的不良毒性，它们的临床应用受到限制。异构体选择性HDAC抑制可能在不产生伴随副作用的情况下对MM产生细胞毒性。在本研究中，我们证明HDAC3的敲低以及一种小分子HDAC3抑制剂BG45通过细胞凋亡引发显著的MM细胞生长抑制，这可由半胱天冬酶和PARP的裂解来证明。重要的是，HDAC3抑制可下调STAT3的磷酸化（酪氨酸705和丝氨酸727）。白细胞介素 - 6和骨髓基质细胞都无法克服HDAC3抑制对p - STAT3和MM细胞生长的这种抑制作用。此外，HDAC3抑制还引发STAT3的高度乙酰化，表明STAT3的磷酸化和乙酰化之间存在串扰信号。重要的是，抑制HDAC3（而非HDAC1或HDAC2）可显著增强硼替佐米诱导的细胞毒性。最后，我们证实BG45单独使用以及与硼替佐米联合使用在人MM的小鼠异种移植模型中可在体内引发显著的肿瘤生长抑制。我们的结果表明HDAC3是一个有前景的治疗靶点，并验证了一种新型HDAC3抑制剂BG45在MM中的原型作用。