title: Class II histone deacetylases play pivotal roles in heat shock protein 90-mediated proteasomal degradation of vascular endothelial growth factor receptors.
abstract: Vascular endothelial growth factor receptors (VEGFRs) perform pivotal roles in both tumor growth and angiogenesis. In this study, we report that histone deacetylase inhibitors (HDIs) induce a reduction in VEGFR1 and VEGFR2 protein expression via the inhibition of class II histone deacetylases (HDACs) in human cancer cell lines. After HDI treatment, VEGFR1 and VEGFR2 were shown to be downregulated in a proteasome-dependent manner. HDI treatment induced a reduction in the binding of heat shock protein (Hsp) 90 to VEGFR1 or VEGFR2, followed by an increase of the binding of Hsp70 to VEGFR1 or VEGFR2. However, we noted no remarkable changes in the binding of Hsp90/Hsp70 to VEGFR3. HDI treatment effectively inhibited the activities of HDAC6 and HDAC10. Furthermore, the knock-down of HDAC6 or HDAC10, which was accomplished via the siRNA transfection, induced depletion of VEGFR1 or VEGFR2 proteins. Overall, these results indicate that HDAC6 and HDAC10 play important roles in Hsp-mediated VEGFR regulation.
authors.affiliation: Laboratory for Cancer Epigenetics and Experimental Therapeutics, Cancer Research Institute, Seoul, Republic of Korea.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Sung-Hak
authors.initials: SH
authors.lastname: Kim
authors.forename: Moon-Chang
authors.initials: MC
authors.lastname: Choi
authors.forename: Juhee
authors.initials: J
authors.lastname: Lee
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
mesh_terms: D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D040262:Receptors, Vascular Endothelial Growth Factor; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases