Histone Deacetylase (HDAC) Inhibition Induces IκB Kinase (IKK)-dependent Interleukin-8/CXCL8 Expression in Ovarian Cancer Cells

• DOI: 10.1074/jbc.m116.771014
• Publication Date: 2017-02-07T01:30:21Z
• Authors: Himavanth R. Gatla; Yue Zou; Mohammad M. Uddin; Bipradeb Singha; Pengli Bu; Ales Vancura; Ivana Vancurova
• Keywords: Vorinostat; Interleukin 8; IκB kinase

Overexpression of the pro-angiogenic chemokine IL-8 (CXCL8) is associated with a poor prognosis in several solid tumors, including epithelial ovarian cancer (EOC). Even though histone deacetylase (HDAC) inhibition has shown remarkable antitumor activity hematological malignancies, it been less effective EOC. Here we report results that may explain decreased efficiency HDAC EOC, based on our data demonstrating specifically induces expression IL-8/CXCL8 SKOV3, CAOV3, and OVCAR3 cells. Suppression or neutralization vorinostat-induced potentiates vorinostat inhibitory effect cell viability proliferation. The induced by EOC cells dependent IκB kinase (IKK) gene-specific recruitment IKKα IKK-dependent p65 NFκB to promoter. In addition, acetylation H3 their promoter occupancy. vivo demonstrate combining IKK inhibitor Bay 117085 significantly reduces tumor growth nude mice compared control untreated either drug alone. Mice combination group had lowest levels murine neutrophil [7/4] antigen, indicating reduced infiltration. Together, mechanism involves IKK, suggesting using inhibitors increase effectiveness when treating other tumors characterized increased expression.