Myosin II Co-Chaperone General Cell UNC-45 Overexpression Is Associated with Ovarian Cancer, Rapid Proliferation, and Motility

Abstract

Both tumor cell proliferation and metastasis are dependent on myosin II. Because UNC-45 is required to chaperone the assembly of a functional myosin II motor, we examined the expression of the general cell (GC) UNC-45 isoform in ovarian tumors. Serous carcinoma expressed elevated levels of GC UNC-45 compared with normal ovarian surface epithelium and benign cystadenoma. High-stage exhibited greater GC UNC-45 expression than low-stage serous carcinoma. Similarly, GC UNC-45 transcripts and protein levels were higher in ovarian cell lines than in immortalized ovarian surface epithelial cells. Elevation of GC UNC-45 levels by ectopic expression enhanced the rate of ovarian cancer cell proliferation, whereas siRNA knockdown of GC UNC-45 suppressed proliferation without altering myosin II levels. GC UNC-45 and myosin II were diffuse within the cytoplasm of confluent interphase cells, but both accumulated together at the cleavage furrow during cytokinesis. GC UNC-45 and myosin II also trafficked to the leading edges of ovarian cancer cells induced to move in a scratch assay. Knockdown of GC UNC-45 reduced the spreading ability of ovarian cancer cells whereas it was enhanced by GC UNC-45 overexpression. In sum, these findings implicate elevated GC UNC-45 protein expression in ovarian carcinoma proliferation and metastasis. Epithelial ovarian cancer is the most lethal gynecological malignancy and the fifth major cause of cancer death among women in the United States. Approximately 70% of ovarian cancer patients are diagnosed with disease that has spread beyond the ovaries when, despite aggressive surgery and chemotherapy, the 5-year survival rate is less than 30%. Ovarian carcinoma rapidly seeds the peritoneal cavity with highly proliferative and invasive cancer cells, and new therapies targeting both of these properties are urgently needed.

UNC45A Confers Resistance to Histone Deacetylase Inhibitors and Retinoic Acid

“…Recently, elevated UNC45A levels have been detected in serous ovarian carcinomas biopsies and UNC45A was found to affect cell proliferation and motility (12). Our data provide a second explanation for the increased UNC45A levels in cancer, as high UNC45A may provide a selective advantage to tumor cells by inhibition of RA-dependent proliferation arrest and differentiation.…”

“…The expression of UNC45A protein in ovarian carcinoma is associated with tumor stage and grade (12). Malignant serous carcinoma expresses elevated levels of UNC45A compared with normal ovarian surface epithelium and benign cysts (12).…”

“…Malignant serous carcinoma expresses elevated levels of UNC45A compared with normal ovarian surface epithelium and benign cysts (12). Furthermore, UNC45A colocalizes with myosin II at the cleavage furrow during cytokinesis and affects cell proliferation and motility (12).…”

Dual function of the UNC-45b Chaperone with myosin and GATA4 in cardiac development

“…UNC-45a expression could not compensate for UNC-45b loss of function during heart development Immunohistochemistry of the wild-type and mutant hearts with monoclonal antibody to UNC-45A, a molecular chaperone for non-muscle myosin II involved in cell proliferation and migration Bazzaro et al, 2007;Guo et al, 2011), showed no differences in the UNC-45a protein accumulation of wild-type and the three mutant hearts (Fig. 7).…”

Differential Turnover of Myosin Chaperone UNC-45A Isoforms Increases in Metastatic Human Breast Cancer

“…UNC-45B was designated the Striated Muscle isoform (SM UNC-45) because its expression is restricted to heart and skeletal muscles. Knockdowns of UNC-45A lead to decreased proliferation of cultured myogenic and ovarian cancer cells, 20,21 whereas knockdowns of UNC-45B disrupt sarcomeric organization in cultured myoblasts and zebrafish. 20,22 Importantly, the elevated expression of the UNC-45A mRNA and protein is found in ovarian tumor samples and derived cell lines.…”