LncRNA <i>MALAT1</i> enhances oncogenic activities of EZH2 in castration-resistant prostate cancer

Wang, Dejie; Ding, Liya; Wang, Liguo; Zhao, Yu; Sun, Zhifu; Karnes, R. Jeffrey; Zhang, Jun; Huang, Haojie

doi:10.18632/oncotarget.5728

Cited by 156 publications

(137 citation statements)

References 34 publications

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“…24, 2018; or activation by modulating their activity (52,54). For example, MALAT1, a known nuclear lncRNA interacts with EZH2, facilitates its occupancy and the H3K27me3 activity on the PRC2 target genes (18), in corroboration to this, we also found that MALAT1 interacts with EZH2 and might facilitate its recruitment on miRNAs regulatory regions. Hence, we propose a molecular model for the functional interplay involving SPINK1, MALAT1 and miR-338-5p/-421, wherein MALAT1 facilitates recruitment of EZH2, which acts as an epigenetic switch and by its histone methyltransferase activity establishes H3K27me3 repressive marks on the promoters of miR-338 and FTX, a miR-421 host gene (Fig.…”

Section: Discussionsupporting

confidence: 82%

“…Since, MALAT1 is known to interact with EZH2 and facilitates its recruitment on its target genes (18), thus to confirm this interaction we performed RNA immunoprecipitation (RIP) assay in 22RV1 cells. Interestingly, 18 immune-complex pulled down by EZH2 antibody show ~22-folds enrichment of MALAT1 as compared to IgG control (Fig. 6H), indicating that MALAT1 directly binds to EZH2, might promote its occupancy, and H3K27me3 repressive marks at miR-338-5p/-421 promoters leading to epigenetic silencing.…”

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confidence: 99%

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Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

Bhatia

Yadav

Tiwari

et al. 2018

Preprint

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PurposeSerine Peptidase Inhibitor, Kazal type-1 (SPINK1) overexpression defines the second most recurrent and aggressive prostate cancer (PCa) subtype. However, the underlying molecular mechanism and pathobiology of SPINK1 in PCa remains largely unknown.Experimental DesignMicroRNA-prediction tools were employed to examine the SPINK1-3’UTR for miRNAs binding. Luciferase reporter assays were performed to confirm the SPINK1-3’UTR binding of shortlisted miR-338-5p/miR-421. Further, miR-338-5p/-421 overexpressing cancer cells (SPINK1-positive) were evaluated for oncogenic properties using cell-based functional assays and mice xenograft model. Global gene expression profiling was performed to unravel the biological pathways altered by miR-338-5p/-421. Immunohistochemistry and RNA in-situ hybridization was carried-out on PCa patients’ tissue microarray for SPINK1 and EZH2 expression respectively. Chromatin immunoprecipitation assay was performed to examine EZH2 occupancy on the miR-338-5p/-421 regulatory regions. Bisulfite sequencing and methylated DNA-immunoprecipitation was performed on PCa cell lines and patients’ specimens.ResultsWe established a critical role of miRNA-338-5p/-421 in post-transcriptional regulation of SPINK1. Ectopic expression of miRNA-338-5p/-421 in SPINK1-positive PCa cells abrogate oncogenic properties including cell-cycle progression, stemness and drug resistance, and show reduced tumor burden and distant metastases in mice model. Importantly, we show SPINK1-positive PCa patients exhibit increased EZH2 expression, suggesting its role in miRNA-338-5p/-421 epigenetic silencing. Furthermore, presence of CpG dinucleotide DNA methylation marks on the regulatory regions of miR-338-5p/-421 in SPINK1-positive PCa cells and patients’ specimens confirms epigenetic silencing.ConclusionOur findings revealed that miRNA-338-5p/-421 are epigenetically silenced in SPINK1-positive PCa, while restoring the expression of these miRNAs using epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis.TRANSLATIONAL IMPACTWe establish a regulatory model involving the functional interplay between SPINK1, miRNA-338-5p/miRNA-421 and EZH2, thereby, revealing hitherto unknown mechanism of SPINK1 up-regulation in SPINK1-positive subtype. Our findings provide a strong rationale for the development of potential therapeutic strategies for SPINK1-positive malignancies. We demonstrate that restoring miRNA-338-5p/miRNA-421 expression using epigenetic drugs including DNMTs inhibitors in combination with HDACs or HKMTs inhibitors or miRNA synthetic mimics in SPINK1-positive prostate cancer abrogate SPINK1-mediated oncogenicity. The major findings of this study will not only advance the prostate cancer field, but will also be valuable for treatment and disease management of other SPINK1-positive malignancies.

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

Bhatia

Yadav

Tiwari

et al. 2018

Preprint

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“…The regulation of EZH2 has been revealed by numerous studies in recent years; for instance, microRNA-138 inhibited tumor growth through repression of EZH2 in NSCLC and osteosarcoma cells (18,19). Furthermore, the long non-coding RNA MALAT1 enhanced the oncogenic activities of EZH2 in castration-resistant prostate cancer (20). These aforementioned findings regarding EZH2 were consistent with the observations of the current study.…”

Section: Discussionsupporting

confidence: 92%

Forkhead box N1 inhibits the progression of non-small cell lung cancer and serves as a tumor suppressor

Wang

et al. 2018

Oncol Lett

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Abstract. Forkhead box N1 (FOXN1) belongs to the FOX family of transcription factors, which comprises a diverse group of winged-helix proteins. FOXN1 is a ubiquitously expressed member that has been implicated in the embryo development, metabolism, aging and cancer. However, little is known regarding the role of FOXN1 in non-small cell lung cancer (NSCLC). The aim of the study was to investigate the function of FOXN1 in NSCLC and examine the relevant mechanism. In the present study, using reverse transcription-quantitative polymerase chain reaction, western blotting, transwell assay, MTT assay, luciferase report assy, it was identified that knockdown of FOXN1 increased the proliferation of A549 and H1299 cells, while overexpression of FOXN1 evidently suppressed the cell growth. A Transwell assay was used to determine the relative cell invasion ability, and it was observed that the invading cells were markedly decreased in the FOXN1 overexpression groups; by contrast, reduced expression of FOXN1 demonstrated the potential to promote cell invasion. Furthermore, lower expression of FOXN1 was observed in NSCLC tissues and cell lines as compared with the adjacent non-tumor tissues or human bronchial epithelial cells, respectively. A higher level of FOXN1 was associated with a better prognosis of NSCLC patients. Quantitative chromatin immunoprecipitation analysis and luciferase reporter gene assays revealed that enhancer of zeste homolog 2 (EZH2) and β-catenin were two target genes of FOXN1. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis indicated that FOXN1 suppressed the expression levels of these target genes at the transcriptional level. In conclusion, the present study demonstrated that FOXN1 served major roles in NSCLC proliferation and invasion by directly repressing EZH2 and β-catenin, which suggested that FOXN1 may function as a tumor suppressor in NSCLC.

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“…7 Among them, lncRNAs have acquired extensive attention, recently, as new regulators in many biological processes, such as transcriptional regulation, 8 differentiation, 9 immune response, 10 metabolism, 11 cell growth, and especially tumorigenesis. 12,13 Moreover, since an increasing number of reports have indicated that their abnormal expression is frequently observed in human cancers, some lncRNAs have been validated as biomarkers for diagnostic, metastasis, recurrence, and poor prognosis, [14][15][16][17] such as MALAT-1 for lung, glioma, gastric, and prostate cancer; [18][19][20][21] HOTAIR for breast, ovarian, pancreatic, and colorectal cancer; [22][23][24][25] and CCAT2 for oral squamous cell carcinoma and bladder cancer. 26,27 Zinc finger antisense 1 (ZFAS1) locus is host to three C/D-box small nucleolar RNAs (snoRNAs), and its transcription initiates from the antisense strand near the 5′ end of the protein-coding gene Znfx1.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of long noncoding RNA zinc finger antisense 1 enhances epithelial–mesenchymal transition in vitro and predicts poor prognosis in glioma

Chen

Zhang

et al. 2017

Tumour Biol.

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Increasing evidence indicates that long noncoding RNAs play important roles in development and progression of various cancers. Zinc finger antisense 1 is a novel long noncoding RNA whose clinical significance, biological function, and underlying mechanism are still undetermined in glioma. In this study, we reported that zinc finger antisense 1 expression was markedly upregulated in glioma and tightly correlated with clinical stage. Moreover, patients with high zinc finger antisense 1 expression had shorter survival. Multivariate Cox regression analysis provided a clue that, probably, zinc finger antisense 1 level could serve as an independent prognostic factor for glioma. Functionally, zinc finger antisense 1 acted as an oncogene in glioma because its knockdown could promote apoptosis and significantly inhibit cell proliferation, migration, and invasion. Furthermore, zinc finger antisense 1 silencing could result in cell cycle arrest at the G0/G1 phase and correspondingly decrease the percentage of S phase cells in both U87 and U251 cell lines. Moreover, it was found that silenced zinc finger antisense 1 could impair migration and invasion by inhibiting the epithelial-mesenchymal transition through reducing the expression of MMP2, MMP9, N-cadherin, Integrin β1, ZEB1, Twist, and Snail as well as increasing E-cadherin level in glioma. Taken together, our data identified that zinc finger antisense 1 might act as a valuable prognostic biomarker and potential therapeutic target for glioma.

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LncRNA MALAT1 enhances oncogenic activities of EZH2 in castration-resistant prostate cancer

Cited by 156 publications

References 34 publications

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

Forkhead box N1 inhibits the progression of non-small cell lung cancer and serves as a tumor suppressor

Upregulation of long noncoding RNA zinc finger antisense 1 enhances epithelial–mesenchymal transition in vitro and predicts poor prognosis in glioma

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