title: Histone deacetylase inhibitor apicidin increases expression of the α-secretase ADAM10 through transcription factor USF1-mediated mechanisms.
abstract: ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) is the α-secretase that is involved in APP (β-amyloid precursor protein) processing. Enhancement of the nonamyloidogenic APP pathway by ADAM10 provides therapeutic potential for Alzheimer's disease (AD). By using high-throughput screening that targeted ADAM10, we determined that apicidin-an inhibitor of HDACs (histone deacetylases)-significantly increased mRNA and protein levels of ADAM10 in SH-SY5Y cells. A luciferase assay revealed that the nucleotides -444 to -300 in the ADAM10 promoter were sufficient to mediate this effect. In addition, knockdown of USF1 (upstream transcription factor 1) and HDAC2/3 prevented apicidin regulation of ADAM10. Moreover, USF1 acetylation was increased by apicidin, which enhanced the association of USF1 with HDAC2/3 and with the ADAM10 promoter. We further found that apicidin did not affect the phosphorylation of ERK or USF1; however, ERK inhibitor U0126 blocked the effect of apicidin on ADAM10. Finally, apicidin increased the level of α-site C-terminal fragment from APP and reduced the production of β-amyloid peptide 1-42. Collectively, our study provides evidence that ADAM10 expression can be regulated by HDAC2/3 inhibitor apicidinviaUSF1-dependent mechanisms in which ERK signaling plays an important role. Thus, HDAC regulation of ADAM10 might shed new light on the understanding of AD pathology.-Hu, X.-T., Zhu, B.-L., Zhao, L.-G., Wang, J.-W., Liu, L., Lai, Y.-J., He, L., Deng, X.-J., Chen, G.-J. Histone deacetylase inhibitor apicidin increases expression of the α-secretase ADAM10 through transcription factor USF1-mediated mechanisms.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Hu
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Bing-Lin
authors.initials: BL
authors.lastname: Zhu
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Li-Ge
authors.initials: LG
authors.lastname: Zhao
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Jing-Wen
authors.initials: JW
authors.lastname: Wang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Lai
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Ling
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Deng
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China woodchen2015@163.com.
authors.forename: Guo-Jun
authors.initials: GJ
authors.lastname: Chen
mesh_terms: D000072197:ADAM10 Protein / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D056572:Histone Deacetylase Inhibitors; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D012333:RNA, Messenger; C497181:USF1 protein, human; D051720:Upstream Stimulatory Factors; C102351:apicidin; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human
keywords: Alzheimer’s disease; ERK; HDAC2/3