DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation

Abstract

Prostate cancer (CaP) is mostly composed of luminal-like differentiated cells, but contains a small subpopulation of basal cells (including stem-like cells), which can proliferate and differentiate into luminal-like cells. In cancers, CpG island hypermethylation has been associated with gene downregulation, but the causal relationship between the two phenomena is still debated. Here we clarify the origin and function of CpG island hypermethylation in CaP, in the context of a cancer cell hierarchy and epithelial differentiation, by analysis of separated basal and luminal cells from cancers. For a set of genes (including GSTP1) that are hypermethylated in CaP, gene downregulation is the result of cell differentiation and is not cancer specific. Hypermethylation is however seen in more differentiated cancer cells and is promoted by hyperproliferation. These genes are maintained as actively expressed and methylation-free in undifferentiated CaP cells, and their hypermethylation is not essential for either tumour development or expansion. We present evidence for the causes and the dynamics of CpG island hypermethylation in CaP, showing that, for a specific set of genes, promoter methylation is downstream of gene downregulation and is not a driver of gene repression, while gene repression is a result of tissue-specific differentiation.

DNA-Methyltransferase 1 Induces Dedifferentiation of Pancreatic Cancer Cells through Silencing of Krüppel-Like Factor 4 Expression

“…DNA hypermethylation is one of the best-understood epigenetic mechanisms that contribute to cancer development and progression (6, 7), which is attributed to either excessive DNA methylation or deficient demethylation; the former is regulated by a family of DNA methyltransferase enzymes (DNMT1, DNMT3A, and DNMT3B) that mediate the transfer of methyl groups from S-adenosylmethionine to the 5 position of cytosine (5-methylcytosine, 5mC) bases in the dinucleotide sequence CpG. Hypermethylation of tumor suppressor genes has been observed in all kinds of cancers and is generally assumed to be functionally equivalent to genetic loss-of-function mutations (8).…”

Telomerase Activity and Telomere Length in Human Benign Prostatic Hyperplasia Stem-like Cells and Their Progeny Implies the Existence of Distinct Basal and Luminal Cell Lineages

“…The lineage of LCs, however, has not been determined in humans, although in vitro we can readily derive luminal cells from basal cells under specific culture conditions [5]. We now propose that basal and luminal cell lineages may develop separately in BPH and speculate that the prostate epithelial SCs can asymmetrically differentiate [8] into distinct basal and luminal progenitor cells, as shown in Figure 2c.…”

“…1, Supplement 1) [4,5] freshly purified from BPH tissues (Supplementary Table 1). The expression of NANOG was also higher in SCs ( Supplementary Fig.…”

Tumor heterogeneity and therapy resistance - implications for future treatments of prostate cancer

“…This is one explanation for such high attrition rate in the drug pipeline; weak, incomplete, unrepresentative or inappropriate models. Also, it has previously been shown that the DNA methylation profile is quite different in cell lines compared to primary cells and indeed between different primary cell subpopulations [29,30] , thus impacting how cells respond to various treatments. Indeed, epigenetic changes can also be induced in response to treatments such as radiation, which relates to radioresistance and radiosensitization [31] .…”