It is well established that cancer-associated epigenetic repression occurs 
concomitant with CpG island hypermethylation and loss of nucleosomes at 
promoters, but the role of nucleosome occupancy and epigenetic reprogramming at 
distal regulatory elements in cancer is still poorly understood. Here, we 
evaluate the scope of global epigenetic alterations at enhancers and insulator 
elements in prostate and breast cancer cells using simultaneous genome-wide 
mapping of DNA methylation and nucleosome occupancy (NOMe-seq). We find that the 
genomic location of nucleosome-depleted regions (NDRs) is mostly cell type 
specific and preferentially found at enhancers in normal cells. In cancer cells, 
however, we observe a global reconfiguration of NDRs at distal regulatory 
elements coupled with a substantial reorganization of the cancer methylome. 
Aberrant acquisition of nucleosomes at enhancer-associated NDRs is associated 
with hypermethylation and epigenetic silencing marks, and conversely, loss of 
nucleosomes with demethylation and epigenetic activation. Remarkably, we show 
that nucleosomes remain strongly organized and phased at many facultative distal 
regulatory elements, even in the absence of a NDR as an anchor. Finally, we find 
that key transcription factor (TF) binding sites also show extensive peripheral 
nucleosome phasing, suggesting the potential for TFs to organize NDRs 
genome-wide and contribute to deregulation of cancer epigenomes. Together, our 
findings suggest that "decommissioning" of NDRs and TFs at distal regulatory 
elements in cancer cells is accompanied by DNA hypermethylation susceptibility 
of enhancers and insulator elements, which in turn may contribute to an altered 
genome-wide architecture and epigenetic deregulation in malignancy.