Dysregulation of p53-RBM25-mediated circAMOTL1L biogenesis contributes to prostate cancer progression through the circAMOTL1L-miR-193a-5p-Pcdha pathway

Abstract

p53, circRNAs and miRNAs are important components of the regulatory network that activates the EMT program in cancer metastasis. In prostate cancer (PCa), however, it has not been investigated whether and how p53 regulates EMT by circRNAs and miRNAs. Here we show that a Amotl1-derived circRNA, termed circAMOTL1L, is downregulated in human PCa, and that decreased circAMOTL1L facilitates PCa cell migration and invasion through downregulating E-cadherin and upregulating vimentin, thus leading to EMT and PCa progression. Mechanistically, we demonstrate that circAMOTL1L serves as a sponge for binding miR-193a-5p in PCa cells, relieving miR-193a-5p repression of Pcdha gene cluster (a subset of the cadherin superfamily members). Accordingly, dysregulation of the circAMOTL1L-miR-193a-5p-Pcdha8 regulatory pathway mediated by circAMOTL1L downregulation contributes to PCa growth in vivo. Further, we show that RBM25 binds directly to circAMOTL1L and induces its biogenesis, whereas p53 regulates EMT via direct activation of RBM25 gene. These findings have linked p53/RBM25-mediated circAMOTL1L-miR-193a-5p-Pcdha regulatory axis to EMT in metastatic progression of PCa. Targeting this newly identified regulatory axis provides a potential therapeutic strategy for aggressive PCa.

circRNA circ‐CCND1 promotes the proliferation of laryngeal squamous cell carcinoma through elevating CCND1 expression via interacting with HuR and miR‐646

“…Recent studies have shown that circRNA functions through different actions, including serving as ‘miRNA sponge’, regulation of transcription and splicing, interacting with RNA‐binding protein, and even translating polypeptide . The most extensively studied is circRNA as a competing endogenous RNA (ceRNA) to effectively sponge miRNA, for example, circ‐HIPK3/miR‐7 in colorectal cancer, circ‐EPSTI1/miR‐942 in ovarian cancer, circ‐ANKS1B/miR‐148/152 in breast cancer and circ‐AMOTL1L/miR‐193a‐5p in prostate cancer . It is well recognized that miRNA is a post‐transcriptional regulator by decreasing mRNA stability or inhibiting translation via directly targeting gene 3′‐UTR .…”

“…16 The most extensively studied is circRNA as a competing endogenous RNA (ceRNA) to effectively sponge miRNA, for example, circ-HIPK3/miR-7 in colorectal cancer, 17 circ-EPSTI1/miR-942 in ovarian cancer, 18 circ-ANKS1B/ miR-148/152 in breast cancer 19 and circ-AMOTL1L/miR-193a-5p in prostate cancer. 20 It is well recognized that miRNA is a post-transcriptional regulator by decreasing mRNA stability or inhibiting translation via directly targeting gene 3′-UTR. 21 In the current study, we identified that circ-CCND1 could simultaneously sponge three miR-646 to diminish the repression of miR-646 on CCND1 3′-UTR, resulting in enhancing the stability of CCND1 mRNA.…”

Extracellular vesicle‐derived circ_SLC19A1 promotes prostate cancer cell growth and invasion through the miR‐497/septin 2 pathway

“…There have been other similar reports in the study of PCa. Yang et al (2019) demonstrated that circAMOTL1L was a sponge that bound miR‐193a‐5p in PCa cells, alleviating the inhibition of miR‐193a‐5p on the Pcdha gene cluster and thus reducing PCa cell invasion and migration by upregulating vimentin and downregulating E‐cadherin. Chen et al (2019) indicated that circAGO2 plays an oncogenic role and promotes tumour progression by enhancing the inhibitory effect of human antigen R (HuR) on AGO2‐miRNA complexes.…”

The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer

“…While, as described above, linear ANRIL affects p53 stability via ARF [141], circANRIL expression impairs rRNA processing and maturation, ultimately leading to nucleolar stress and p53 activation [170]. The activation of p53 is also affected by other circRNAs, including: i) circ_0000263, which sponges miR-150-5p, in turn causing the up-regulation of the p53 inhibitor MDM4 [171]; ii) circ_0055538, whose loss in oral squamous cell carcinoma attenuates p53's pro-apoptotic response [172]; and iii) circAMOTL1L, whose downregulation promotes prostate cancer progression by impairing the p53dependent regulation of EMT [173]. Despite the numerous reports demonstrating the functional interactions between circRNAs and the p53 pathway (Table 3), further efforts are still needed to show whether circRNAs can also affect the stability or the activity of the remaining members of the p53 family and what consequences this interplay may have in human cancers and other biological processes.…”

“…[171] circ_0055538 tumour suppressor required for p53-dependent apoptosis [172] circAMOTL1L tumour suppressor mediating p53 suppression of EMT [173] circANRIL causes p53 activation via nucleolar stress [170] PINT p53 target encoding a small tumour suppressive peptide [169]…”