Dataset Information

Regulation of CD133 by HDAC6 promotes ?-catenin signaling to suppress cancer cell differentiation.

ABSTRACT: The pentaspan membrane glycoprotein CD133 marks lineage-specific cancer progenitor cells and is associated with poor prognosis in a number of tumor types. Despite its utility as a cancer progenitor cell marker, CD133 protein regulation and molecular function remain poorly understood. We find that the deacetylase HDAC6 physically associates with CD133 to negatively regulate CD133 trafficking down the endosomal-lysosomal pathway for degradation. We further demonstrate that CD133, HDAC6, and the central molecule of the canonical Wnt signaling pathway, ?-catenin, can physically associate as a ternary complex. This association stabilizes ?-catenin via HDAC6 deacetylase activity, which leads to activation of ?-catenin signaling targets. Downregulation of either CD133 or HDAC6 results in increased ?-catenin acetylation and degradation, which correlates with decreased proliferation in vitro and tumor xenograft growth in vivo. Given that CD133 marks progenitor cells in a wide range of cancers, targeting CD133 may be a means to treat multiple cancer types.

SUBMITTER: Mak AB

PROVIDER: S-EPMC3590846 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Regulation of CD133 by HDAC6 promotes β-catenin signaling to suppress cancer cell differentiation.

Mak Anthony B AB Nixon Allison M L AM Kittanakom Saranya S Stewart Jocelyn M JM Chen Ginny I GI Curak Jasna J Gingras Anne-Claude AC Mazitschek Ralph R Neel Benjamin G BG Stagljar Igor I Moffat Jason J

Cell reports 20121019 4

The pentaspan membrane glycoprotein CD133 marks lineage-specific cancer progenitor cells and is associated with poor prognosis in a number of tumor types. Despite its utility as a cancer progenitor cell marker, CD133 protein regulation and molecular function remain poorly understood. We find that the deacetylase HDAC6 physically associates with CD133 to negatively regulate CD133 trafficking down the endosomal-lysosomal pathway for degradation. We further demonstrate that CD133, HDAC6, and the ce ...[more]

PMID: 23084749

Similar Datasets

Project description:BackgroundEpigenetic control is essential for maintenance of tissue hierarchy and correct differentiation. In cancer, this hierarchical structure is altered and epigenetic control deregulated, but the relationship between these two phenomena is still unclear. CD133 is a marker for adult stem cells in various tissues and tumour types. Stem cell specificity is maintained by tight regulation of CD133 expression at both transcriptional and post-translational levels. In this study we investigated the role of epigenetic regulation of CD133 in epithelial differentiation and cancer.MethodsDNA methylation analysis of the CD133 promoter was done by pyrosequencing and methylation specific PCR; qRT-PCR was used to measure CD133 expression and chromatin structure was determined by ChIP. Cells were treated with DNA demethylating agents and HDAC inhibitors. All the experiments were carried out in both cell lines and primary samples.ResultsWe found that CD133 expression is repressed by DNA methylation in the majority of prostate epithelial cell lines examined, where the promoter is heavily CpG hypermethylated, whereas in primary prostate cancer and benign prostatic hyperplasia, low levels of DNA methylation, accompanied by low levels of mRNA, were found. Moreover, differential methylation of CD133 was absent from both benign or malignant CD133+/?2?1integrinhi prostate (stem) cells, when compared to CD133-/?2?1integrinhi (transit amplifying) cells or CD133-/?2?1integrinlow (basal committed) cells, selected from primary epithelial cultures. Condensed chromatin was associated with CD133 downregulation in all of the cell lines, and treatment with HDAC inhibitors resulted in CD133 re-expression in both cell lines and primary samples.ConclusionsCD133 is tightly regulated by DNA methylation only in cell lines, where promoter methylation and gene expression inversely correlate. This highlights the crucial choice of cell model systems when studying epigenetic control in cancer biology and stem cell biology. Significantly, in both benign and malignant prostate primary tissues, regulation of CD133 is independent of DNA methylation, but is under the dynamic control of chromatin condensation. This indicates that CD133 expression is not altered in prostate cancer and it is consistent with an important role for CD133 in the maintenance of the hierarchical cell differentiation patterns in cancer.

Dataset Information

Regulation of CD133 by HDAC6 promotes ?-catenin signaling to suppress cancer cell differentiation.

Publications

Regulation of CD133 by HDAC6 promotes β-catenin signaling to suppress cancer cell differentiation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets