Silencing HDAC1 Expression Regulates Extracellular Regulated Protein Kinases/Mitogen-Activated Protein Kinase Signaling Activation and Enhances Chemosensitivity of Ovarian Carcinoma

Abstract

Objective: Cisplatin (DDP)-based therapy is frequently employed as a first-line chemotherapy for ovarian carcinoma (OC). ERK/mitogen-activated protein kinase (MAPK), as a widely studied axis with cancer-promoting action, is reported to be essential in mediating chemoresistance in many cancer cells. This study investigated the effect of HDAC1 expression on the chemosensitivity of OC via regulation of the ERK/MAPK axis. Methods: Fifty-eight cases of OC and adjacent tissue specimens were acquired, as well as the survival data of patients with OC in the Cancer Genome Atlas. To detect HDAC1 in tissues, a HDAC1-DNA probe was constructed, and patients with different HDAC1 levels were analyzed for survival. HDAC1 levels were also detected in SKOV3 and SKOV3/DDP cells. HDAC1 siRNA was used to interfere with HDAC1 expression, after which the sensitivity to DDP sensitivity and changes in apoptosis of tumor cells were detected using the MTT assay and flow cytometry, respectively. Western blotting quantified the expression of ERK/MAPK axis-related proteins. Results: HDAC1 was highly expressed in OC tissues, with a high expression significantly related to adverse outcomes of patients. Compared with that in SKOV3 cells, SKOV3/DDP cells showed decreased sensitivity to DDP and increased HDAC1 expression. After transfection of HDAC1-siRNA, SKOV3/DDP cell sensitivity to DDP increased, p38 MAPK, ERK1/2, and JNK phosphorylation levels decreased, and the apoptosis rate increased markedly; transfection with an ERK agonist reversed the inhibitory action of HDAC1-siRNA against cells. Conclusions: Silencing HDAC1 expression significantly reduced the chemoresistance of DDP-resistant OC cell lines and promoted apoptosis, and its mechanism is related to inhibition of ERK/MAPK activation.