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TGF-β1 promotes epithelial-to-mesenchymal transition and stemness of prostate cancer cells by inducing PCBP1 degradation and alternative splicing of CD44.
- Source :
-
Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2021 Feb; Vol. 78 (3), pp. 949-962. Date of Electronic Publication: 2020 May 21. - Publication Year :
- 2021
-
Abstract
- CD44 is a marker of cancer stem cell (CSC) in many types of tumors. Alternative splicing of its 20 exons generates various CD44 isoforms that have different tissue specific expression and functions, including the CD44 standard isoform (CD44s) encoded by the constant exons and the CD44 variant isoforms (CD44v) with variant exon insertions. Switching between the CD44v and CD44s isoforms plays pivotal roles in tumor progression. Here we reported a novel mechanism of CD44 alternative splicing induced by TGF-β1 and its connection to enhanced epithelial-to-mesenchymal transition (EMT) and stemness in human prostate cancer cells. TGF-β1 treatment increased the expression of CD44s and N-cadherin while decreased the expression of CD44v and E-cadherin in DU-145 prostate cancer cells. Other EMT markers and cancer stem cell markers were also upregulated after TGF-β1 treatment. RNAi knockdown of CD44 reversed the phenotype, which could be rescued by overexpressing CD44s but not CD44v, indicating the alternatively spliced isoform CD44s mediated the activity of TGF-β1 treatment. Mechanistically, TGF-β1 treatment induced the phosphorylation, poly-ubiquitination, and degradation of PCBP1, a well-characterized RNA binding protein known to regulate CD44 splicing. RNAi knockdown of PCBP1 was able to mimic TGF-β1 treatment to increase the expression of CD44s, as well as the EMT and cancer stem cell markers. In vitro and in vivo experiments were performed to show that CD44s promoted prostate cancer cell migration, invasion, and tumor initiation. Taken together, we defined a mechanism by which TGF-β1 induces CD44 alternative splicing and promotes prostate cancer progression.
- Subjects :
- Alternative Splicing
Animals
Cadherins genetics
Cadherins metabolism
Cell Line, Tumor
Cell Movement drug effects
DNA-Binding Proteins antagonists & inhibitors
DNA-Binding Proteins genetics
Humans
Hyaluronan Receptors antagonists & inhibitors
Hyaluronan Receptors genetics
Male
Mice
Mice, Nude
Prostatic Neoplasms drug therapy
Prostatic Neoplasms metabolism
Prostatic Neoplasms pathology
Protein Isoforms antagonists & inhibitors
Protein Isoforms genetics
Protein Isoforms metabolism
Protein Kinase Inhibitors pharmacology
RNA Interference
RNA, Small Interfering metabolism
RNA, Small Interfering therapeutic use
RNA-Binding Proteins antagonists & inhibitors
RNA-Binding Proteins genetics
Smad3 Protein antagonists & inhibitors
Smad3 Protein genetics
Smad3 Protein metabolism
Transplantation, Heterologous
DNA-Binding Proteins metabolism
Epithelial-Mesenchymal Transition drug effects
Hyaluronan Receptors metabolism
RNA-Binding Proteins metabolism
Transforming Growth Factor beta1 pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1420-9071
- Volume :
- 78
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cellular and molecular life sciences : CMLS
- Publication Type :
- Academic Journal
- Accession number :
- 32440711
- Full Text :
- https://doi.org/10.1007/s00018-020-03544-5