PKCι regulates nuclear YAP1 localization and ovarian cancer tumorigenesis

Atypical protein kinase C iota (PKC iota) is an oncogene in lung and ovarian cancer. The PKC iota gene PRKCI is targeted for frequent tumorspecific copy number gain (CNG) in both lung squamous cell carcinoma (LSCC) and ovarian serous carcinoma (OSC). We recently demonstrated that in LSCC cells PRKCI CNG functions to drive transformed growth and tumorigenicity by activating PKC iota-dependent cell autonomous Hedgehog (Hh) signaling. Here, we assessed whether OSC cells harboring PRKCI CNG exhibit similar PKC iota-dependent Hh signaling. Surprisingly, we find that whereas PKC iota is required for the transformed growth of OSC cells harboring PRKCI CNG, these cells do not exhibit PKC iota-dependent Hh signaling or Hh-dependent proliferation. Rather, transformed growth of OSC cells is regulated by PKC iota-dependent nuclear localization of the oncogenic transcription factor, YAP1. Lentiviral shRNA-mediated knockdown (KD) of PKC iota leads to decreased nuclear YAP1 and increased YAP1 binding to angiomotin (AMOT), which sequesters YAP1 in the cytoplasm. Biochemical analysis reveals that PKC iota directly phosphorylates AMOT at a unique site, Thr750, whose phosphorylation inhibits YAP1 binding. Pharmacologic inhibition of PKC iota decreases YAP1 nuclear localization and blocks OSC tumor growth in vitro and in vivo. Immunohistochemical analysis reveals a strong positive correlation between tumor PKC iota expression and nuclear YAP1 in primary OSC tumor samples, indicating the clinical relevance of PKC iota-YAP1 signaling. Our results uncover a novel PKC iota-AMOT-YAP1 signaling axis that promotes OSC tumor growth, and provide a rationale for therapeutic targeting of this pathway for treatment of OSC.