Conserved Two-Step Regulatory Mechanism of Human Epithelial Differentiation

Abstract

SummaryHuman epithelia are organized in a hierarchical structure, where stem cells generate terminally differentiated cells via intermediate progenitors. This two-step differentiation process is conserved in all tissues, but it is not known whether a common gene set contributes to its regulation. Here, we show that retinoic acid (RA) regulates early human prostate epithelial differentiation by activating a tightly coexpressed set of 80 genes (e.g., TMPRSS2). Response kinetics suggested that some of these genes could be direct RA targets, whereas others are probably responding indirectly to RA stimulation. Comparative bioinformatic analyses of published tissue-specific microarrays and a large-scale transcriptomic data set revealed that these 80 genes are not only RA responsive but also significantly coexpressed in many human cell systems. The same gene set preferentially responds to androgens during terminal prostate epithelial differentiation, implying a cell-type-dependent interplay between RA and tissue-specific transcription factor-mediated signaling in regulating the two steps of epithelial differentiation.

Inhibition of the glucocorticoid receptor results in an enhanced miR-99a/100-mediated radiation response in stem-like cells from human prostate cancers

“…We therefore investigated whether induction of DNA repair via the miR-99a/100-SMARA5/SMARCD1 axis was due to either EMT or de-differentiation of CB cells into SC. We inhibited miR-99a/100 in CB cells and looked for EMT or dedifferentiation, using commonly used EMT and previously reported PCa and normal stem cell markers [10, 11, 35, 46–48]. None of these markers showed any changes after inhibition of miR-99a/100 (Figure 5A, 5B, 5C).…”

“…We have previously shown that androgen regulated genes in luminal cells can also be controlled by a different steroid hormone in androgen-independent basal cells [48]. A previous study suggested that miR-99a/100 are suppressed by androgens in androgen-dependent cells with a luminal phenotype [30].…”

Targeting phenotypic heterogeneity in benign prostatic hyperplasia

“…The hierarchy of the prostate epithelium has been debated for some time (60–64). Adult, fully differentiated prostate glands are lined with a continuous layer of cuboidal basal epithelium and an adjacent secretory layer of tall columnar luminal epithelium.…”

“…This cell surface marker-based hierarchical clustering of cell ‘types’ doesn’t account for the probable presence of progenitor and intermediate sub-types within each master lineage (60). The 20% reduction in prostate volume achieved by luminal epithelial-targeted 5ARI treatment is reversible when the treatment is stopped (67, 68), which suggests a potential role for stem cells in BPH (69–71).…”

The many ways to make a luminal cell and a prostate cancer cell

“…It may seem counterintuitive to characterize basal cells as ‘differentiated,’ but it has been recognized by some groups that the 95–99% of basal cells that do not display self-renewing progenitor characteristics are an independent lineage termed ‘committed’ basal cells (Maitland et al . 2011, Rane et al . 2014).…”