Keratin 17 Maintains Proliferation by Binding p27KIP1 and Facilitating its Nuclear Export

Previous work in our lab identified keratin 17 (K17) overexpression as a negative prognostic marker in cervical cancer but the mechanisms by which K17 contributes to cancer-related signaling remain unknown. A hallmark of cancer cells is their ability to sustain proliferation by evading cell cycle regulatory programs controlled by tumor suppressors. By in vitro studies and biochemical approaches in cervical cancer cell lines, we found that K17 expression promotes aberrant cell cycle progression. Silencing K17 induced G1 arrest by a 3 to 5-fold nuclear accumulation of p27^KIP1, a cyclin-dependent kinase inhibitor (CKI) and key controller of G1/S phase transition. After identifying the nuclear localization of K17 during G1 phase, we hypothesised that nuclear-K17 might bind to and promote the subsequent degradation of p27^KIP1. To determine potential K17-binding partners, we performed immunoprecipitation assays and found that endogenous nuclear-localized K17 coimmunoprecipitated with p27^KIP1 in cervical cancer cells. Furthermore, we confirmed this binding by quantifying colocalization of K17 and p27^KIP1 in the nucleus of cells in G1, using super-resolution structured illumination microscopy. Complementary experiments in our lab further tested that K17 acts as an export adaptor of nuclear p27^KIP1. Thus, these studies have identified an oncogenic and novel role for K17 promoting deregulation of G1 cell cycle arrest by mediating p27^KIP1 nuclear export and subsequent degradation, elucidating a potential mechanism through which overexpression of K17 results in poorer patient prognosis.