Mechanistic role of metal-responsive transcription factor-1 (MTF1) in cadmium-induced prostate carcinogenesis

Our previous report emphasized that chronic exposure to cadmium (10 µM) over one year led to the transformation of benign prostatic hyperplasia (BPH1) cells into malignancy through the ZIC2 signaling pathway (cerebellar zinc pathway). However, the upstream mechanisms that trigger this transformation have yet to be fully elucidated. The present study suggests that cadmium exposure induces metal regulatory element-binding transcription factor-1 (MTF1), which activates ZIC2 in BPH1 cells. Interestingly, knocking out ZIC2 expression did not affect MTF1 levels, indicating that MTF1 acts upstream of the ZIC2 signaling pathway. To further investigate the MTF-1/ZIC2 relationship, we overexpressed MTF-1 in untransformed BPH1 cells leading to the induction of ZIC2 along with other stem cell markers, such as ALDH1A1, Nanog, and CD44. This overexpression also facilitated spheroid formation. Conversely, silencing MTF1 expression in transformed cells inhibited spheroid formation and also reduced survival rate. It diminished the expression of stem cell and epithelial-to-mesenchymal transition markers and tumor growth in nude mice. Transcriptomic analysis of MTF1 silenced xenograft tumors confirmed these findings. Using CRISPR-Cas9 to knock out ZIC2 also prevented tumor formation in nude mice. These results emphasize the critical role of MTF1 in the oncogenic process and its involvement in the ZIC2-mediated transformation associated with Cd-induced malignant changes.