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Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer.

 Yunhee Cho  ;  Hyun-Woo Lee  ;  Hyeok-Gu Kang  ;  Hye-Young Kim  ;  Seok-Jun Kim  ;  Kyung-Hee Chun 
 ONCOTARGET , Vol.6(11) : 8709-8721, 2015 
Journal Title
Issue Date
Active Transport, Cell Nucleus ; Animals ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology* ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic ; Heterografts ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; Hyaluronan Receptors/biosynthesis ; Hyaluronan Receptors/chemistry ; Hyaluronan Receptors/genetics ; Hyaluronan Receptors/physiology* ; Lung Neoplasms/secondary ; Mice ; Nanog Homeobox Protein ; Neoplasm Proteins/biosynthesis ; Neoplasm Proteins/chemistry ; Neoplasm Proteins/genetics ; Neoplasm Proteins/physiology* ; Neoplastic Stem Cells/metabolism* ; Neoplastic Stem Cells/pathology ; Octamer Transcription Factor-3/genetics ; Octamer Transcription Factor-3/metabolism ; Protein Interaction Mapping ; Protein Structure, Tertiary ; RNA Interference ; RNA, Messenger/biosynthesis ; RNA, Neoplasm/biosynthesis ; RNA, Small Interfering/genetics ; Recombinant Fusion Proteins/metabolism ; SOXB1 Transcription Factors/genetics ; SOXB1 Transcription Factors/metabolism ; Specific Pathogen-Free Organisms ; Spheroids, Cellular ; Transcription, Genetic ; Transfection
CD44 ; breast cancer ; intracellular domain ; stemness factors
CD44 plays a role in the progression of tumors and is expressed in cancer stem cells (CSCs). However, the mechanisms underlying the crosstalk of CD44 with stemness genes in CSC maintenance remains unclear. In this study, we demonstrated how the cleaved intracellular domain of CD44 (CD44ICD) activates stemness factors such as Nanog, Sox2 and Oct4, and contributes to the tumorigenesis of breast cancer. We have found that the overexpression of CD44ICD increased mammosphere formation in breast cancer cells. Treatment with a γ-secretase inhibitor (GSI), which blocks the cleavage of CD44ICD, interfered with mammosphere formation. Interestingly, CD44ICD decreased the expression levels and nuclear localization of stemness factors, but overexpression of CD44ICD reversed these effects. In addition, we showed that nuclear localization of CD44ICD is important for transcriptional activation of the stemness factors. Furthermore, CD44ICD-overexpressed cells exhibited strong tumorigenecity and greater metastatic potential than did the control cells or CD44-depleted cells in vivo in mice models. Taken together, it was supposed that CD44 promotes tumorigenesis through the interaction and nuclear-translocation of its intracellular domain and stemness factors. We suggest that the prevention of cleavage and nuclear-translocation of CD44ICD is a potential target in treating breast cancer.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hyeok Gu(강혁구) ORCID logo https://orcid.org/0000-0002-3187-6844
Kim, Seok Jun(김석준)
Chun, Kyung Hee(전경희) ORCID logo https://orcid.org/0000-0002-9867-7321
Cho, Yun Hee(조윤희)
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