9641

IKBKE

inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon;IKBKE;inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon

I-kappa-B kinase epsilon|IKK-epsilon|IKK-related kinase epsilon|inducible I kappa-B kinase|inducible IkappaB kinase|inhibitor of nuclear factor kappa-B kinase subunit epsilon

1q32.1

protein-coding

Inhibitor of IkappaB kinases (IKK) are key regulators of NF-kappaB signaling. Three IKK isoforms-alpha, beta, and epsilon-have been linked to oncogenesis, yet the precise components of NF-kappaB signaling in ovarian cancer have not yet been dissected. We surveyed 120 ovarian cancer specimens for IKK-epsilon expression. Notably, cytoplasmic expression was elevated in metastatic lesions relative to primary tumors (P = 0.03). Therefore, we hypothesized that IKK-epsilon drives ovarian cancer metastasis. IKK-epsilon was identified previously as a breast cancer oncogene and was associated with poor clinical outcome in ovarian cancer. We now define an ovarian cancer-specific IKK-epsilon-regulated gene expression signature using stably expressed short hairpin RNA targeting IKK-epsilon. pathway analysis of the signature indicated that IKK-epsilon regulates expression of genes involved in cell motility and inflammation. We further showed that IKK-epsilon depletion in metastatic ovarian cancer cell lines decreased growth, adhesion, and invasion. Consistently, human xenografts depleted of IKK-epsilon in mice showed decreased aggressiveness, whereas overexpression of IKK-epsilon in a less invasive ovarian cancer cell line increased metastasis in vivo. Taken together, these data provide evidence that IKK-epsilon is a key coordinator of invasion and metastasis programs in ovarian cancer. Inhibition of IKK-epsilon signaling thus emerges as a viable therapeutic strategy in women whose ovarian cancer shows aberrant activation of this pathway.