Androgens regulate CALCA gene expression in the prostate by methylation of CALCA Promoter-Reference-Cited by-同舟云学术

Androgens regulate CALCA gene expression in the prostate by methylation of CALCA Promoter

Published:2022-11-11 Issue: Volume: Page:
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Author:

Masud Neshat¹,Chaudhary Jaideep²,Shah Girish V.¹

Affiliation:

1. University of Louisiana at Monroe

2. Clark Atlanta University

Abstract

Abstract 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.

Publisher

Research Square Platform LLC

Reference134 articles.

1. J Ccancer Research and Clinical Oncology

2. "Calcitonin induces stem cell-like phenotype in prostate cancer cells;Aldahish A;Endocr Relat Cancer,2019

3. Stem cell-like-cancer cells are key drivers of tumor growth, metastasis, and relapse of cancer following remission. Prostate stem cell-like cancer cells isolated from human prostate cancer (PC) biopsies express CD44+/alpha2beta1 hi/CD133 + cell surface markers and can self-renew in vitro. Expression of calcitonin (CT) and its receptor (CTR) is frequently elevated in PCs and activation of CT-CTR axis in non-invasive PC cells induces an invasive phenotype. We investigated whether CT-CTR autocrine axis induces stem cell-like phenotype in two PC cell lines. CT-CTR axis in these cell lines was activated by enforced expression of CTR. The cells were then examined for the changes in the expression of CD44 and CD133, collagen adherence, tumorigenic, metastatic and repopulating characteristics. The activation of CT-CTR axis led to a large increase in adherence to collagen and a remarkable increase of CD44 and CD133 in PC-3 and LNCaP cells. This was accompanied by a strong increase in tumorigenic, metastatic and repopulation properties of PC cells. However, the mutation of CTR-C PDZ-binding site in CTR almost abolished CTR-mediated increases in stem cell-like characteristics of PC cells. These results support an important role for CT-CTR axis in the progression of PC from localized cancer to an aggressive form, and a majority of proinvasive CTR actions may be mediated through its interaction with its partner protein at the PDZ-binding site. These results suggest that CT/CTR can serve as a valuable target to prevent the generation of stem-like PC cells.

4. "DNA methylation and the regulation of gene transcription;Attwood JT;Cell Mol Life Sci,2002

5. The regulation of gene transcription is not simply dependent on the presence or absence of DNA-binding transcription factors that turn genes on or off, but also involves processes determining the ability of transcription factors to gain access to and bind their target DNA. Methylation of DNA cytosine bases leads to the inaccessibility of DNA regulatory elements to their transcription factors by a number of mechanisms. Our understanding of DNA methylation has advanced rapidly in recent years with the identification of an increasingly large number of novel proteins involved in this process. These include methylcytosine-binding proteins as well as additional members of the DNA methyltransferase family. The creation of mice with targeted deletions in a number of genes involved in DNA methylation has further elucidated the functions of many of these proteins. The characterization of complexes that contain proteins known to be involved in DNA methylation has led to the identification of additional proteins, especially those involved in histone deacetylation, indicating that DNA methylation and histone deacetylation very likely act in a synergistic fashion to regulate gene transcription. Finally, the implication of DNA methylation in tumorigenesis and the realization that some congenital diseases are caused by deficiency of proteins involved in DNA methylation has confirmed the importance of this process in regulating gene expression.