Abstract
Estrogen and hypoxia promote an aggressive phenotype in prostate cancer (PCa), driving transcription of progression-associated genes. Here, we molecularly dissect the contribution of long non-coding RNA H19 to PCa metastatic potential under combined stimuli, a topic largely uncovered. The effects of estrogen and hypoxia on H19 and cell adhesion molecules’ expression were investigated in PCa cells and PCa-derived organotypic slice cultures (OSCs) by qPCR and Western blot. The molecular mechanism was addressed by chromatin immunoprecipitations, overexpression, and silencing assays. PCa cells’ metastatic potential was analyzed by in vitro cell-cell adhesion, motility test, and trans-well invasion assay. We found that combined treatment caused a significant H19 down-regulation as compared with hypoxia. In turn, H19 acts as a transcriptional repressor of cell adhesion molecules, as revealed by up-regulation of both β3 and β4 integrins and E-cadherin upon H19 silencing or combined treatment. Importantly, H19 down-regulation and β integrins induction were also observed in treated OSCs. Combined treatment increased both cell motility and invasion of PCa cells. Lastly, reduction of β integrins and invasion was achieved through epigenetic modulation of H19-dependent transcription. Our study revealed that estrogen and hypoxia transcriptionally regulate, via H19, cell adhesion molecules redirecting metastatic dissemination from EMT to a β integrin-mediated invasion.
Highlights
Prostate cancer (PCa) is one of the most common cancers in developed countries [1]
We found that H19 is significantly induced by hypoxia and by estrogens in hormone-driven tumor cells, such as breast and prostate cancer cells (Figure S1)
chromatin immunoprecipitation [42] (ChIP)-Seq data (Figure 1a) showed that the H19 genomic region was highly enriched in endothelial nitric oxide synthase (eNOS)-peaks, especially after 17β-estradiol (E2) treatment, and that these peaks were present in prostate epithelial luminal cells derived from aggressive primary cancer (C27IM, exclusively expressing beta isoform of the estrogen receptor [39,42,43]), but not in normal human primary umbilical vein endothelial cells (HUVECs)
Summary
Prostate cancer (PCa) is one of the most common cancers in developed countries [1]. Widespread prostate-specific antigen (PSA) screening has revealed that most patients present localized disease [2], for which radical prostatectomy (RP) and radiation therapy (RT) are standard treatments. Within 10 years, 20%–40% of post-RP [3] and 30%–50% of post-RT [4] patients will experience biochemical recurrence On average, this precedes the appearance by eight years after RP of clinical metastases [5,6] that are the major cause of complications and death [7]. Estrogen/estrogen receptors signaling plays a fundamental role in PCa carcinogenesis and progression [9,10]. Hormone naïve prostate cancer, unlike high grade prostate in situ neoplasia, generally retains high levels of ERβ expression, even in lymph node and bone metastasis [10], in favor of a pro-tumoral role, depending on cancer stage [11,12]. ERβ is extensively expressed in the secretory luminal cell types, in both benign and neoplastic lesions, as well as in prostate cancer stem cells
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