A novel DNA-binding motif in prostate tumor overexpressed-1 (PTOV1) required for the expression of ALDH1A1 and CCNG2 in cancer cells. (28th June 2019)

• Record Type: Journal Article
• Authors: Maggio, Valentina; Cánovas, Verónica; Félix, Alex J.; Gómez, Valentí; de Torres, Inés; Semidey, María Eugenia; Morote, Juan; Noé, Verónique; Ciudad, Carlos J.; Paciucci, Rosanna
• Is Part Of: Cancer letters. Volume 452(2019)
• Page Start: 158
• Page End: 167
• Publication Date: 2019-06-28
• Subjects: PTOV1 -- DNA-Binding motif -- AT-Hook -- Aggressive prostate cancer -- Chromatin immunoprecipitation -- EMSA; PTOV1 Prostate Tumor Overexpressed-1 -- PCa Prostate Cancer -- CRPC Castration Resistant Prostate Cancer -- ADT Androgen Deprivation Therapy -- ALDH1A1 Aldehyde Dehydrogenase 1 family member A1 -- CCNG2 Cyclin G2 -- DKK1 Dickkopf WNT signaling pathway inhibitor 1 -- HES1 Hes family bHLH transcription factor 1 -- HMGA1 High Mobility Group Protein A1 -- RACK1 Receptor of Activated protein C Kinase 1; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.03.019
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: PTOV1 is a transcription and translation regulator and a promoter of cancer progression. Its overexpression in prostate cancer induces transcription of drug resistance and self-renewal genes, and docetaxel resistance . Here we studied PTOV1 ability to directly activate the transcription of ALDH1A1 and CCNG2 by binding to specific promoter sequences. Chromatin immunoprecipitation and electrophoretic mobility shift assays identified a DNA-binding motif inside the PTOV-A domain with similarities to known AT-hooks that specifically interacts with ALDH1A1 and CCNG2 promoters. Mutation of this AT-hook- like sequence significantly decreased the expression of ALDH1A1 and CCNG2 promoted by PTOV1. Immunohistochemistry revealed the association of PTOV1 with mitotic chromosomes in high grade prostate, colon, bladder, and breast carcinomas. Overexpression of PTOV1, ALDH1A1, and CCNG2 significantly correlated with poor prognosis in prostate carcinomas and with shorter relapse-free survival in colon carcinoma. The previously described interaction with translation complexes and its direct binding to ALDH1A1 and CCNG2 promoters found here reveal the PTOV1 capacity to modulate the expression of critical genes at multiple levels in aggressive cancers. Remarkably, the AT-hook motifs in PTOV1 open possibilities for selective targeting its nuclear and/or cytoplasmic activities. Highlights: A novel DNA-binding motif in PTOV1 is required for ALDH1A1 and CCNG2 overexpression. PTOV1 is a direct transcriptional activator of gene expression in prostate cancer. Distinct DNA- RNA-binding motifs might direct PTOV1 nuclear and cytoplasmic actions. PTOV1, ALDH1A1, CCNG2 expression associated with prostate and colon cancer bad prognosis.