PKCι regulates nuclear YAP1 localization and ovarian cancer tumorigenesis.
Atypical protein kinase Cι (PKCι) is an oncogene in lung and ovarian cancer. The PKCι gene PRKCI is targeted for frequent tumor-specific 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 PKCι-dependent cell autonomous Hedgehog (Hh) signaling. Here, we assessed whether OSC cells harboring PRKCI CNG exhibit similar PKCι-dependent Hh signaling. Surprisingly, we find that whereas PKCι is required for the transformed growth of OSC cells harboring PRKCI CNG, these cells do not exhibit PKCι-dependent Hh signaling or Hh-dependent proliferation. Rather, transformed growth of OSC cells is regulated by PKCι-dependent nuclear localization of the oncogenic transcription factor, YAP1. Lentiviral shRNA-mediated knockdown (KD) of PKCι leads to decreased nuclear YAP1 and increased YAP1 binding to angiomotin (AMOT), which sequesters YAP1 in the cytoplasm. Biochemical analysis reveals that PKCι directly phosphorylates AMOT at a unique site, Thr750, whose phosphorylation inhibits YAP1 binding. Pharmacologic inhibition of PKCι decreases YAP1 nuclear localization and blocks OSC tumor growth in vitro and in vivo. Immunohistochemical analysis reveals a strong positive correlation between tumor PKCι expression and nuclear YAP1 in primary OSC tumor samples, indicating the clinical relevance of PKCι-YAP1 signaling. Our results uncover a novel PKCι-AMOT-YAP1 signaling axis that promotes OSC tumor growth, and provide a rationale for therapeutic targeting of this pathway for treatment of OSC.
Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
Y
Y
Wang
Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
V
V
Justilien
Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
K I
KI
Brennan
Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
L
L
Jamieson
Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
N R
NR
Murray
Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
A P
AP
Fields
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000091082:Angiomotins; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D000091102:YAP-Signaling Proteins; D000099293:Protein Kinase C-lambda
D048868:Adaptor Proteins, Signal Transducing; D000091082:Angiomotins; D018797:Cell Cycle Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D011493:Protein Kinase C; D000091102:YAP-Signaling Proteins; D000099293:Protein Kinase C-lambda; C423985:AMOT protein, human; C486223:Yap1 protein, mouse