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Expression of calcitonin (CT) and its receptor (CTR) is frequently elevated in prostate cancer (PC), and activation of CT–CTR axis in non-invasive PC cells induces an invasive phenotype. However, the regulation of CT gene (CALCA) expression in the prostate has not been investigated. We investigated the regulation of CALCA gene expression in multiple PC cell lines and primary PC specimens. The results show that androgen-activated androgen receptor (AR) represses CALCA gene expression, and this can be abolished either by the knock-out of AR or the treatment with AR antagonists. Chromatin immunoprecipitation assay identified that AR induces methylation of CpG64 region of distal CALCA gene promoter, and this was prevented by knock-out of AR. This region was examined in multiple PC cell lines and primary PC specimens. PC cells that lacked CT mRNA abundance displayed methylated CpG64 region, and this methylation was partially reversed either with the knock-out of AR or incubation with AR antagonist. Primary prostate tissue specimens from normal or benign prostatic hyperplasia displayed methylated CALCA gene promoter. In contrast, those from advanced PCs displayed at least partially demethylated CALCA gene promoter. These results explain our earlier results that CALCA gene expression in the prostate is silent in benign prostate epithelium but is active in malignant prostate epithelium, and high level of CALCA gene expression in advanced PC. These results raise a possibility that elevated CALCA gene expression in malignant prostate may indicate progressive loss of AR expression and/or AR signaling.

Prostate-derived calcitonin (CT) and its receptor induce tumorigenicity and increase metastatic potential of prostate cancer (PC). CT-inducible genes in human prostate were identified by subtraction hybridization. Among these genes, zinc finger protein like 1 (ZFPL1) protein was interesting since it was abundantly expressed in malignant prostates but was almost absent in benign prostates. ZFPL1 expression was upregulated by CT and androgens, and ZFPL1 protein was secreted by prostate tumor cells through exosomal secretion. Serum levels of ZFPL1 in cancer patients were at least 4-fold higher than those in the sera of cancer-free individuals. Cell biology of ZFPL1 suggests its localization in Golgi bodies and exosomes, and its colocalization with chromogranin A and CD44. These results suggested that ZFPL1 is secreted by tumor cells of neuroendocrine (NE)/stem cell phenotype. The knockdown of endogenous ZFPL1 in (PC) cells led to a remarkable decrease in cell proliferation, and invasion while increasing their apoptosis. As expected, the overexpression of ZFPL1 in prostate cells had an opposite effect on these functions. The knockdown of ZFPL1 in PC cells also decreased Akt phosphorylation, suggesting the actions of ZFPL1 may be mediated through the PI3K-Akt pathway. Moreover, the present results revealed that ZFPL1 is released by tumors cells of NE or androgen-independent phenotype and its serum levels are significantly higher in cancer patients, suggesting that it may serve as a blood-based non-invasive biomarker of aggressive PC.