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Post-translational modification of OCT4 in breast cancer tumorigenesis

 Yunhee Cho  ;  Hyeok Gu Kang  ;  Seok-Jun Kim  ;  Seul Lee  ;  Sujin Jee  ;  Sung Gwe Ahn  ;  Min Jueng Kang  ;  Joon Seon Song  ;  Joon-Yong Chung  ;  Eugene C. Yi  ;  Kyung-Hee Chun 
 CELL DEATH AND DIFFERENTIATION, Vol.25(10) : 1781-1795, 2018 
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Recurrence and drug resistance of breast cancer are still the main reasons for breast cancer-associated deaths. Cancer stem cell (CSC) model has been proposed as a hypothesis for the lethality of breast cancer. Molecular mechanisms underlying CSC maintenance are still unclear. In this study, we generated mammospheres derived from breast cancer MDA-MB231 cells and MCF7 cells to enrich CSCs and performed DNA microarray analysis. We found that the expression of carboxy terminus of HSP70-interacting protein (CHIP) E3 ubiquitin ligase was significantly downregulated in breast CSCs. CHIP depletion increased mammosphere formation, whereas CHIP overexpression reversed this effect. We identified interactomes by mass spectrometry and detected CHIP directly interacted with OCT4, a stemness factor. CHIP overexpression decreased OCT4 stability through proteasomal degradation. CHIP induced OCT4 ubiquitination, whereas H260Q, a catalytic CHIP mutant, did not. Interestingly, we determined that OCT4 was ubiquitinated at lysine 284, and CHIP overexpression did not degrade K284R mutant OCT4. CHIP overexpression decreased the proliferation and side population of breast cancer cells, but these were not occurred in K284R mutant OCT4 overexpressed cells. Only 1000 cells showing CHIP depletion or OCT4 overexpression sufficiently generated breast tumors and lung metastases in xenografted mice. Ubiquitination-defective mutant of OCT4(K284R) overexpressed cells drastically generated tumor burdens in mice. Patients with breast cancer who showed low CHIP expression had poor survival probability. Taken together, we suggest that CHIP-induced OCT4 ubiquitination is important in breast CSCs. Regulation of CHIP expression and OCT4 protein stability is a considerable approach for breast cancer therapy.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hyeok Gu(강혁구) ORCID logo https://orcid.org/0000-0002-3187-6844
Ahn, Sung Gwe(안성귀) ORCID logo https://orcid.org/0000-0002-8778-9686
Chun, Kyung Hee(전경희) ORCID logo https://orcid.org/0000-0002-9867-7321
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