Shan Bin, Yao Tso-pang, Nguyen Hong T, Zhuo Ying, Levy Dawn R, Klingsberg Ross C, Tao Hui, Palmer Michael L, Holder Kevin N, Lasky Joseph A
Department of Medicine and Tulane Cancer Center, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
J Biol Chem. 2008 Jul 25;283(30):21065-73. doi: 10.1074/jbc.M802786200. Epub 2008 May 21.
The aberrant expression of transforming growth factor (TGF)-beta1 in the tumor microenvironment and fibrotic lesions plays a critical role in tumor progression and tissue fibrosis by inducing epithelial-mesenchymal transition (EMT). EMT promotes tumor cell motility and invasiveness. How EMT affects motility and invasion is not well understood. Here we report that HDAC6 is a novel modulator of TGF-beta1-induced EMT. HDAC6 is a microtubule-associated deacetylase that predominantly deacetylates nonhistone proteins, including alpha-tubulin, and regulates cell motility. We showed that TGF-beta1-induced EMT is accompanied by HDAC6-dependent deacetylation of alpha-tubulin. Importantly, inhibition of HDAC6 by small interfering RNA or the small molecule inhibitor tubacin attenuated the TGF-beta1-induced EMT markers, such as the aberrant expression of epithelial and mesenchymal peptides, as well as the formation of stress fibers. Reduced expression of HDAC6 also impaired the activation of SMAD3 in response to TGF-beta1. Conversely, inhibition of SMAD3 activation substantially impaired HDAC6-dependent deacetylation of alpha-tubulin as well as the expression of EMT markers. These findings reveal a novel function of HDAC6 in EMT by intercepting the TGF-beta-SMAD3 signaling cascade. Our results identify HDAC6 as a critical regulator of EMT and a potential therapeutic target against pathological EMT, a key event for tumor progression and fibrogenesis.
转化生长因子（TGF）-β1在肿瘤微环境和纤维化病变中的异常表达，通过诱导上皮-间质转化（EMT）在肿瘤进展和组织纤维化中起关键作用。EMT促进肿瘤细胞的运动性和侵袭性。EMT如何影响运动性和侵袭性尚不清楚。在此，我们报道HDAC6是TGF-β1诱导的EMT的一种新型调节因子。HDAC6是一种与微管相关的去乙酰化酶，主要使包括α-微管蛋白在内的非组蛋白去乙酰化，并调节细胞运动性。我们发现TGF-β1诱导的EMT伴随着HDAC6依赖的α-微管蛋白去乙酰化。重要的是，小分子干扰RNA或小分子抑制剂tubacin对HDAC6的抑制减弱了TGF-β1诱导的EMT标志物，如上皮和间质肽的异常表达以及应力纤维的形成。HDAC6表达降低也损害了对TGF-β1反应时SMAD3的激活。相反，抑制SMAD3激活显著损害了HDAC6依赖的α-微管蛋白去乙酰化以及EMT标志物的表达。这些发现揭示了HDAC6通过阻断TGF-β-SMAD3信号级联在EMT中的新功能。我们的结果确定HDAC6是EMT的关键调节因子，也是针对病理性EMT的潜在治疗靶点，病理性EMT是肿瘤进展和纤维化形成的关键事件。
