Abstract
BackgroundCalcification of adamantinomatous craniopharyngioma (ACP) often causes problems with tumor resection, leading to a high incidence of deadly complications and tumor recurrence. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are 2 key enzymes that regulate histone acetylation and play important roles in tumor development. However, the roles of HAT and HDAC in the calcification and osteoblastic differentiation of ACP are not known.MethodsIn this study, primary cells were isolated from ACP tissues, and calcification was induced with bone morphogenetic protein 2 (Bmp2). HDAC3 expression was assessed in 12 tissue samples by Western blotting and immunohistochemistry. ACP calcification was assessed by Alizarin red staining. A luciferase reporter assay was performed to examine the interaction between miR-181b and the 3’-untranslated region of the polycomb chromobox 4 (CBX4) gene.ResultsOur results showed that the expression of HDAC3 was increased in the calcified ACP samples, but inhibition of HDAC3 promoted ACP cell calcification and osteoblastic differentiation. Mechanistically, HDAC3 nuclear translocation was suppressed by Bmp2, leading to Runx2 protein expression and Osterix, osteocalcin (OCN), osteopontin (OPN), and alkaline phosphatase (ALP) mRNA expression. In addition, this process was suppressed by CBX4, which stabilized the nuclear localization of HDAC3. miR-181b, the expression of which was increased in Bmp2-induced ACP cells, directly targeted and decreased CBX4 expression and inhibited the nuclear localization of HDAC3.ConclusionsOur results demonstrate that Bmp2 increases miR-181b levels to directly target and inhibit CBX4 expression, leading to a reduction in the CBX4-dependent regulation of HDAC3 nuclear translocation, which results in Runx2 activation/osteoblastic differentiation and calcium deposition in ACP. Further studies targeting these cascades may contribute to therapeutic interventions used for recurrent ACP.9tuZg5nvh-wSqYQ-ZFLrLrVideo
Highlights
Calcification of adamantinomatous craniopharyngioma (ACP) often causes problems with tumor resection, leading to a high incidence of deadly complications and tumor recurrence
HDAC3 expression is increased in calcified ACP To explore the effects of histone acetylation with respect to ACP calcification, we measured the Histone acetyltransferase (HAT) and HDAC3 levels in bone morphogenetic protein 2 (Bmp2)-treated ACP cells
Bmp2 suppressed HDAC3 nuclear translocation to activate the Runt-related transcription factor 2 (Runx2) pathway and promote osteoblastic differentiation of ACP To examine the relationship between HDAC3 expression and ACP calcification, siRNA was used to knock-down the expression of HDAC3 (Fig. 3A)
Summary
Calcification of adamantinomatous craniopharyngioma (ACP) often causes problems with tumor resection, leading to a high incidence of deadly complications and tumor recurrence. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) are 2 key enzymes that regulate histone acetylation and play important roles in tumor development. Yan et al Cell Communication and Signaling (2022) 20:3 tumor-adjacent structures, such as the hypothalamus, internal carotid artery, optic nerve and pituitary stalk, calcification often causes problems during tumor resection, leading to a high incidence of deadly complications and tumor recurrence (Fig. 1A-D) [1, 2]. Cell pattern of ACP is different from SPCP (Fig. 1E, F). This difference may be explained by the theory that ACP originates from odontogenic rests associated with remnants of Rathke’s pouch, while SPCP develops from buccal mucosa rests [3, 4]
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