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Human kallikrein 6 ( KLK6 ) was identified based on its transient upregulation in a primary breast tumor and its subsequent silencing in a metastatic tumor from the same patient. The molecular mechanism(s) underlying the deregulated expression of  KLK6  during cancer progression are currently unknown. Here, we provide evidence that aberrant expression of  KLK6  is regulated at the level of transcription by multiple cooperating mechanisms.  KLK6  can be reactivated in non-expressing breast cancer cells by treatment with 5-aza-2′-deoxycytidine (5-aza-dC), a compound causing DNA demethylation. Trichostatin A (TSA), an inhibitor of histone deacetylases, resulted in moderate induction of  KLK6  only in MDA-MB-231 cells. However, combined 5-aza-dC/TSA treatment resulted in synergistic activation of  KLK6 . We show that  KLK6  inactivation is associated with hypermethylation of specific CpG dinucleotides located in the  KLK6  proximal promoter and overexpression with complete demethylation. These results indicate a causal role of DNA methylation and chromatin structure in cancer-associated loss of  KLK6  expression. In some breast cancer cell lines,  KLK6  expression could be restored by the vitamin D3 analog EB1089. Our data indicate that transcriptional deregulation of  KLK6  in cancer cells during breast cancer progression is complex and certainly not uniform in different tumors, involving epigenetic mechanisms as well as pathways regulated by nuclear receptors. This allows for the pharmacological modulation of  KLK6  with potential therapeutic implications.

Multiple mechanisms underlie the aberrant expression of the human kallikrein 6 gene in breast cancer