Hippo pathway effector Yap is an ovarian cancer oncogene.
The Hippo pathway regulates organ size and tumorigenesis in Drosophila and mammals and is altered in a variety of human cancers, yet it remains unclear if the Hippo pathway is of prognostic significance to cancer patients. Here we show that the key targets of Hippo signaling, transcriptional coactivators Yki and Yap, play a conserved role in promoting ovarian cancer in flies and humans, respectively. Whereas studies linking Yap to cancer in other tissues have focused on overall Yap levels, we show for the first time that subcellular levels of Yap show an exceptionally strong association with poor patient survival. Specifically, high levels of nuclear Yap (nYap), or low levels of cytoplasmic phosphorylated Yap (cpYap), associated with poor survival from ovarian cancer. Patients with both high nYap and low cpYap had ∼50% lower 5-year survival, and this combination is an independent prognostic marker for survival, with an exceptionally high hazard ratio of 7.8. We find that Yap2 is the predominantly expressed Yap isoform in both the ovarian surface epithelium (OSE) and epithelial ovarian cancers. Overexpression of Yap2 and phosphorylation-defective Yap2-5SA in immortalized OSE cells resulted in increased cell proliferation, resistance to cisplatin-induced apoptosis, faster cell migration, and anchorage-independent growth, whereas Yap knockdown resulted in increased sensitivity to cisplatin-induced apoptosis. Findings argue that the Hippo signaling pathway defines an important pathway in progression of ovarian cancer.
Department of Molecular and Human Genetics, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
Chad A
CA
Hall
Runsheng
R
Wang
Jiangyong
J
Miao
Esther
E
Oliva
Xiaoyun
X
Shen
Thomas
T
Wheeler
Susan G
SG
Hilsenbeck
Sandra
S
Orsulic
Scott
S
Goode
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000502:physiology*; D009857:Oncogenes / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D010766:Phosphorylation; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000502:physiology*; D055815:Young Adult
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D002945:Cisplatin