PMID- 27321186
OWN - NLM
STAT- MEDLINE
DCOM- 20170926
LR  - 20220409
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 36
IP  - 4
DP  - 2017 Jan 26
TI  - PKCiota regulates nuclear YAP1 localization and ovarian cancer tumorigenesis.
PG  - 534-545
LID - 10.1038/onc.2016.224 [doi]
AB  - Atypical protein kinase Ciota (PKCiota) is an oncogene in lung and ovarian cancer. The 
      PKCiota 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 PKCiota-dependent cell autonomous Hedgehog 
      (Hh) signaling. Here, we assessed whether OSC cells harboring PRKCI CNG exhibit 
      similar PKCiota-dependent Hh signaling. Surprisingly, we find that whereas PKCiota is 
      required for the transformed growth of OSC cells harboring PRKCI CNG, these cells 
      do not exhibit PKCiota-dependent Hh signaling or Hh-dependent proliferation. Rather, 
      transformed growth of OSC cells is regulated by PKCiota-dependent nuclear 
      localization of the oncogenic transcription factor, YAP1. Lentiviral 
      shRNA-mediated knockdown (KD) of PKCiota leads to decreased nuclear YAP1 and 
      increased YAP1 binding to angiomotin (AMOT), which sequesters YAP1 in the 
      cytoplasm. Biochemical analysis reveals that PKCiota directly phosphorylates AMOT at 
      a unique site, Thr750, whose phosphorylation inhibits YAP1 binding. Pharmacologic 
      inhibition of PKCiota decreases YAP1 nuclear localization and blocks OSC tumor 
      growth in vitro and in vivo. Immunohistochemical analysis reveals a strong 
      positive correlation between tumor PKCiota expression and nuclear YAP1 in primary 
      OSC tumor samples, indicating the clinical relevance of PKCiota-YAP1 signaling. Our 
      results uncover a novel PKCiota-AMOT-YAP1 signaling axis that promotes OSC tumor 
      growth, and provide a rationale for therapeutic targeting of this pathway for 
      treatment of OSC.
FAU - Wang, Y
AU  - Wang Y
AD  - Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL, 
      USA.
FAU - Justilien, V
AU  - Justilien V
AD  - Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL, 
      USA.
FAU - Brennan, K I
AU  - Brennan KI
AD  - Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL, 
      USA.
FAU - Jamieson, L
AU  - Jamieson L
AD  - Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL, 
      USA.
FAU - Murray, N R
AU  - Murray NR
AD  - Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL, 
      USA.
FAU - Fields, A P
AU  - Fields AP
AD  - Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL, 
      USA.
LA  - eng
GR  - P50 CA136393/CA/NCI NIH HHS/United States
GR  - R01 CA081436/CA/NCI NIH HHS/United States
GR  - R21 CA204938/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20160620
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (AMOT protein, human)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Angiomotins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Isoenzymes)
RN  - 0 (Membrane Proteins)
RN  - 0 (Microfilament Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (YAP-Signaling Proteins)
RN  - 0 (Yap1 protein, mouse)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.13 (protein kinase C lambda)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/*metabolism
MH  - Angiomotins
MH  - Animals
MH  - Carcinogenesis/*metabolism/pathology
MH  - Cell Cycle Proteins
MH  - Cell Line, Tumor
MH  - Female
MH  - Heterografts
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/metabolism
MH  - Isoenzymes/genetics/*metabolism
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - Mice, Nude
MH  - Microfilament Proteins
MH  - Ovarian Neoplasms/genetics/*metabolism/pathology
MH  - Phosphoproteins/genetics/*metabolism
MH  - Protein Kinase C/genetics/*metabolism
MH  - Signal Transduction
MH  - Transfection
MH  - YAP-Signaling Proteins
PMC - PMC5173453
MID - NIHMS787447
COIS- The authors declare that they have no conflicts of interest to disclose.
EDAT- 2016/06/21 06:00
MHDA- 2017/09/28 06:00
PMCR- 2017/01/27
CRDT- 2016/06/21 06:00
PHST- 2016/01/12 00:00 [received]
PHST- 2016/05/06 00:00 [revised]
PHST- 2016/05/15 00:00 [accepted]
PHST- 2016/06/21 06:00 [pubmed]
PHST- 2017/09/28 06:00 [medline]
PHST- 2016/06/21 06:00 [entrez]
PHST- 2017/01/27 00:00 [pmc-release]
AID - onc2016224 [pii]
AID - 10.1038/onc.2016.224 [doi]
PST - ppublish
SO  - Oncogene. 2017 Jan 26;36(4):534-545. doi: 10.1038/onc.2016.224. Epub 2016 Jun 20.