title: HPOB, an HDAC6 inhibitor, attenuates corticosterone-induced injury in rat adrenal pheochromocytoma PC12 cells by inhibiting mitochondrial GR translocation and the intrinsic apoptosis pathway.
abstract: High levels of glucocorticoids (GCs) have been reported to damage normal hippocampal neurons, and such damage has been positively correlated with major depression (MD) and chronic stress. Our previous study showed that HDAC6 might be a potential target to regulate GC-induced glucocorticoid receptor (GR) translocation to the mitochondria and subsequent apoptosis. In the present study, we investigated the effect of HPOB, a selective HDAC6 inhibitor, on corticosterone (Cort)-induced apoptosis and explored the possible mechanism of action of HPOB in rat adrenal pheochromocytoma (PC12) cells, which possesses typical neuron features and expresses high levels of glucocorticoid receptors. We demonstrated that pre-treatment with HPOB remarkably reduced Cort-induced cytotoxicity and confirmed the anti-apoptotic effect of HPOB via the caspase-3 activity assay and H33342/PI and TUNEL double staining. Mechanistically, we demonstrated that HPOB reversed the Cort-induced elevation of GR levels in the mitochondria and blocked concomitant mitochondrial dysfunction and the intrinsic apoptosis pathway. Furthermore, HPOB was shown to attenuate expression of the multi-chaperone machinery (Hsp90-Hop-Hsp70) and cooperate with mitochondrial translocase of the outer/inner membrane (TOM/TIM) complex recruitment by triggering hyperacetylation of Hsps through HDAC6 inhibition. Considering all of these findings, the neuroprotective effect of HPOB demonstrated the crucial role of HDAC6 inhibition in reducing Cort-induced apoptosis in PC12 cells. The data further suggested that the anti-apoptotic activity of HDAC6 inhibition against the mitochondria-mediated impairment pathway might be mechanistically linked to the hyperacetylation of Hsps and consequent suppression of GR translocation to the mitochondria.
authors: Brain Center, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen, 518035, China.
authors: Zong-Yang
authors: ZY
authors: Li
authors: Shantou University Medical College, Shantou, 515041, China.
authors: Qing-Zhong
authors: QZ
authors: Li
authors: Brain Center, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen, 518035, China.
authors: Lei
authors: L
authors: Chen
authors: Brain Center, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen, 518035, China.
authors: Bao-Dong
authors: BD
authors: Chen
authors: Brain Center, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen, 518035, China.
authors: Ce
authors: C
authors: Zhang
authors: Brain Center, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen, 518035, China.
authors: Xiang
authors: X
authors: Wang
authors: Brain Center, Shenzhen Key Laboratory of Neurosurgery, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen, 518035, China. Electronic address: wpli@szu.edu.cn.
authors: Wei-Ping
authors: WP
authors: Li
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D003345:Corticosterone / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D018841:HSP90 Heat-Shock Proteins; D000073864:Histone Deacetylase 6 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000378:metabolism*; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D011965:Receptors, Glucocorticoid; C545556:HDAC6 protein, rat; D000073864:Histone Deacetylase 6; D003345:Corticosterone
keywords: Glucocorticoid receptor; HDAC6; HPOB; Hsp90; Mitochondrial translocation