Downregulation of CHIP promotes ovarian cancer metastasis by inducing Snail-mediated epithelial-mesenchymal transition.
Sun-Mi ParkSeung-Ho ParkKi-Jun RyuIn-Kyu KimHyeontak HanHyo-Jin KimSeon-Hee KimKeun-Seok HongHyemin KimMinju KimBok Im ChoJeong Doo HeoNa Hyun KimEun Mi HwangJae-Yong ParkJong In YookHee Jun ChoCheol HwangboKwang Dong KimHoseok SongJiyun YooPublished in: Molecular oncology (2019)
The epithelial-mesenchymal transition (EMT) plays a pivotal role in the conversion of early-stage tumors into invasive malignancies. The transcription factor Snail, an extremely unstable protein whose subcellular levels are regulated by many E3 ubiquitin ligases, promotes EMT as well as associated pathological characteristics including migration, invasion, and metastasis. Through yeast two-hybrid screening, we identified the carboxyl terminus of Hsc70-interacting protein (CHIP) as a novel Snail ubiquitin ligase that interacts with Snail to induce ubiquitin-mediated proteasomal degradation. Inhibition of CHIP expression increases Snail protein levels, induces EMT, and enhances in vitro migration and invasion as well as in vivo metastasis of ovarian cancer cells. In turn, Snail depletion abrogates all phenomena induced by CHIP depletion. Finally, Snail and CHIP expression is inversely correlated in ovarian tumor tissues. These findings establish the CHIP-Snail axis as a post-translational mechanism of EMT and cancer metastasis regulation.
Keyphrases
- epithelial mesenchymal transition
- transforming growth factor
- signaling pathway
- high throughput
- circulating tumor cells
- early stage
- binding protein
- transcription factor
- poor prognosis
- small molecule
- lymph node
- squamous cell carcinoma
- amino acid
- papillary thyroid
- radiation therapy
- rectal cancer
- quantum dots
- sensitive detection