Choudhary Vivek, Olala Lawrence O, Kagha Karen, Pan Zhi-Qiang, Chen Xunsheng, Yang Rong, Cline Abigail, Helwa Inas, Marshall Lauren, Kaddour-Djebbar Ismail, McGee-Lawrence Meghan E, Bollag Wendy B
Charlie Norwood VA Medical Center, Augusta, Georgia, USA; Department of Physiology, Augusta University, Augusta, Georgia, USA; Department of Medicine (Dermatology), Augusta University, Augusta, Georgia, USA.
Charlie Norwood VA Medical Center, Augusta, Georgia, USA; Department of Physiology, Augusta University, Augusta, Georgia, USA.
J Invest Dermatol. 2017 Sep;137(9):1935-1944. doi: 10.1016/j.jid.2017.04.031. Epub 2017 May 16.
Aquaporin- (AQP) 3, a water and glycerol channel, plays an important role in epidermal function, with studies showing its involvement in keratinocyte proliferation, differentiation, and migration and in epidermal wound healing and barrier repair. Increasing speculation about the use of histone deacetylase (HDAC) inhibitors to treat skin diseases led us to investigate HDAC's role in the regulation of AQP3. The broad-spectrum HDAC inhibitor suberoylanilide hydroxamic acid induced AQP3 mRNA and protein expression in a dose- and time-dependent manner in normal keratinocytes. The SAHA-induced increase in AQP3 levels resulted in enhanced [H]glycerol uptake in normal but not in AQP3-knockout keratinocytes, confirming that the expressed AQP3 was functional. Use of HDAC inhibitors with different specificities limited our exploration of the responsible HDAC member to HDAC1, HDAC2, or HDAC3. Cre-recombinase-mediated knockdown and overexpression of HDAC3 suggested a role for HDAC3 in suppressing AQP3 expression basally. Further investigation implicated p53 as a transcription factor involved in regulating HDAC inhibitor-induced AQP3 expression. Thus, our study supports the regulation of AQP3 expression by HDAC3 and p53. Because suberoylanilide hydroxamic acid is already approved to treat cutaneous T-cell lymphoma, it could potentially be used as a therapy for skin diseases like psoriasis, where AQP3 is abnormally expressed.
水通道蛋白-（AQP）3是一种水和甘油通道，在表皮功能中发挥重要作用，研究表明它参与角质形成细胞的增殖、分化和迁移以及表皮伤口愈合和屏障修复。对使用组蛋白脱乙酰酶（HDAC）抑制剂治疗皮肤疾病的猜测不断增加，促使我们研究HDAC在AQP3调节中的作用。广谱HDAC抑制剂辛二酰苯胺异羟肟酸在正常角质形成细胞中以剂量和时间依赖性方式诱导AQP3 mRNA和蛋白表达。SAHA诱导的AQP3水平升高导致正常角质形成细胞而非AQP3基因敲除角质形成细胞中[H]甘油摄取增加，证实表达的AQP3具有功能。使用具有不同特异性的HDAC抑制剂使我们将对相关HDAC成员的探索局限于HDAC1、HDAC2或HDAC3。Cre重组酶介导的HDAC3敲低和过表达表明HDAC3在基础上抑制AQP3表达中起作用。进一步研究表明p53作为参与调节HDAC抑制剂诱导的AQP3表达的转录因子。因此，我们的研究支持HDAC3和p53对AQP3表达的调节。由于辛二酰苯胺异羟肟酸已被批准用于治疗皮肤T细胞淋巴瘤，它可能潜在地用作治疗AQP3异常表达的皮肤病如银屑病的疗法。
