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

doi:10.18632/oncotarget.3325

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

Oncotarget. 2015 Apr 20;6(11):8709-21. doi: 10.18632/oncotarget.3325.

Authors

Yunhee Cho^{1

2}, Hyun-Woo Lee¹, Hyeok-Gu Kang^{1

2}, Hye-Young Kim^{1

3}, Seok-Jun Kim^{1

2}, Kyung-Hee Chun^{1

2}

Affiliations

¹ Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Korea.
² Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seodaemun-gu, Seoul 120-752, Korea.
³ Department of Biochemistry, College of Life Science and Biotechnology, Seodaemun-gu, Seoul 120-752, Korea.

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.

Keywords: CD44; breast cancer; intracellular domain; stemness factors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

CD44 protein, human
Homeodomain Proteins
Hyaluronan Receptors
NANOG protein, human
Nanog Homeobox Protein
Neoplasm Proteins
Octamer Transcription Factor-3
POU5F1 protein, human
RNA, Messenger
RNA, Neoplasm
RNA, Small Interfering
Recombinant Fusion Proteins
SOX2 protein, human
SOXB1 Transcription Factors