title: Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer.
abstract: 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.
authors.affiliation: Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Korea.|Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seodaemun-gu, Seoul 120-752, Korea.
authors.forename: Yunhee
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Korea.
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Korea.|Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seodaemun-gu, Seoul 120-752, Korea.
authors.forename: Hyeok-Gu
authors.initials: HG
authors.lastname: Kang
authors.affiliation: Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Korea.|Department of Biochemistry, College of Life Science and Biotechnology, Seodaemun-gu, Seoul 120-752, Korea.
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Korea.|Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seodaemun-gu, Seoul 120-752, Korea.
authors.forename: Seok-Jun
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Korea.|Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seodaemun-gu, Seoul 120-752, Korea.
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Chun
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D018874:Spheroids, Cellular; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: C497483:CD44 protein, human; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors
keywords: CD44; breast cancer; intracellular domain; stemness factors