A
disintegrin and
metalloprotease domain-containing
protein 12 (ADAM-12) is upregulated in many human
cancers and promotes
cancer metastasis. Increased urinary level of ADAM-12 in breast and
bladder cancers correlates with
disease progression. However, the mechanism of its induction in
cancer remains less understood. Previously, we reported a
Z-DNA-forming negative regulatory
element (NRE) in ADAM-12 that functions as a transcriptional suppressor to maintain a low-level expression of ADAM-12 in most normal cells. We now report here that overexpression of ADAM-12 in triple-negative MDA-MB-231
breast cancer cells and
breast cancer tumors is likely due to a marked loss of this
Z-DNA-mediated transcriptional suppression function. We show that
Z-DNA suppressor operates by interaction with methyl-CpG-
binding protein, MeCP2, a prominent epigenetic regulator, and two members of the
nuclear factor 1 family of
transcription factors, NF1C and NF1X. While this tripartite interaction is highly prevalent in normal breast epithelial cells, both in vitro and in vivo, it is significantly lower in
breast cancer cells. Western blot analysis has revealed significant differences in the levels of these 3
proteins between normal mammary epithelial and
breast cancer cells. Furthermore, we show, by NRE mutation analysis, that interaction of these
proteins with the NRE is necessary for effective suppressor function. Our findings unveil a new epigenetic regulatory process in which
Z-DNA/MeCP2/NF1 interaction leads to transcriptional suppression, loss of which results in ADAM-12 overexpression in
breast cancer cells.