Keratin-17 Promotes p27^KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility

Abstract

Keratins that are overexpressed selectively in human carcinomas may offer diagnostic and prognostic utility. In this study, we show that high expression of keratin-17 (K17) predicts poor outcome in patients with cervical cancer, at early or late stages of disease, surpassing in accuracy either tumor staging or loss of p27^KIP1 as a negative prognostic marker in this setting. We investigated the mechanistic basis for the biologic impact of K17 through loss- and gain-of-function experiments in human cervix, breast, and pancreatic cancer cells. Specifically, we determined that K17 functions as an oncoprotein by regulating the subcellular localization and degradation of p27^KIP1. We found that K17 was released from intermediate filaments and translocated into the nucleus via a nuclear localization signal (NLS), specific among keratins, where it bound p27^KIP1 during G₁ phase of the cell cycle. p27^KIP1 lacks a nuclear export signal (NES) and requires an adaptor for CRM1 binding for nuclear export. In K17, we defined and validated a leucine-rich NES that mediated CRM1 binding for export. Cervical cancer cells expressing K17 mutations in its NLS or NES signals exhibited an increase in levels of nuclear p27^KIP1, whereas cells expressing wild-type K17 exhibited a depletion in total endogenous p27^KIP1. In clinical specimens of cervical cancer, we confirmed that the expressions of K17 and p27^KIP1 were inversely correlated, both across tumors and within individual tumors. Overall, our findings establish that K17 functions specially among keratins as an oncoprotein by controlling the ability of p27^KIP1 to influence cervical cancer pathogenesis. Cancer Res; 75(17); 1–13. ©2015 AACR.