LncRNA HOTAIR Enhances the Androgen-Receptor-Mediated Transcriptional Program and Drives Castration-Resistant Prostate Cancer

Zhang, Ali; Zhao, Jonathan C.; Kim, Jung; Fong, Ka Wing; Yang, Yeqing; Chakravarti, Debabrata; Mo, Yin Yuan; Yu, Jindan

doi:10.1016/j.celrep.2015.08.069

Cited by 296 publications

(262 citation statements)

References 32 publications

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“…http://dx.doi.org/10.1101/376277 doi: bioRxiv preprint first posted online Jul. 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.…”

Section: Discussionsupporting

confidence: 71%

“…Numerous lncRNAs have been reported to be dysregulated in prostate cancer (51,52), for instance, PCGEM1 and PRNCR1 are highly expressed in aggressive PCa and enhance the AR-mediated gene activation program (53). Furthermore, MALAT1 renders cell cycle arrest in G1/S transition and mitotic phase by modulating the expression of E2F1 and B-MYB (25).…”

Section: Discussionmentioning

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: 71%

Section: Discussionmentioning

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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“…A possible mechanism for such migration and the cell growth-promoting ability of SOCS2-AS1 may be the modulation of AR signaling by SOCS2-AS1. As in several lncRNAs such as HOTAIR (22) and PCGEM1 (58), Our ChIP analysis indicated that SOCS2-AS1 may be involved in the modification of AR for recruiting epigenetic modifiers without changing the AR protein level or binding to genome. However, TNFSF10 is up-regulated even in the absence of DHT by SOCS2-AS1 knockdown (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…PCAT-1 was characterized as a novel prostate-specific lncRNA, regulator of cell proliferation, and target of the polycomb repressive complex 2 (PRC2) (15). HOTAIR RNA binds to AR protein to block the interaction with the E3 ubiquitin ligase MDM2, thereby preventing protein degradation and AR activation (22).…”

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confidence: 99%

Androgen-induced Long Noncoding RNA (lncRNA) SOCS2-AS1 Promotes Cell Growth and Inhibits Apoptosis in Prostate Cancer Cells

Misawa

Takayama

Urano

et al. 2016

Journal of Biological Chemistry

135

108

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Long noncoding RNAs (lncRNA) have been associated with the development of cancer. However, the interplay between lncRNAs and androgen receptor (AR) signaling in prostate cancer is still unclear. Here, we identified lncRNAs induced by androgen in AR-positive prostate cancer cells, where induction was abolished by AR knockdown as well as an anti-androgen, bicalutamide. By combining these data, we identified an androgen-regulated lncRNA, suppressor of cytokine signaling 2-antisense transcript 1 (SOCS2-AS1), the expression of which was higher in castration-resistant prostate cancer model cells, i.e. long-term androgen-deprived (LTAD) cells, than in parental androgen-dependent LNCaP cells. SOCS2-AS1 promoted castration-resistant and androgen-dependent cell growth. We found that SOCS2-AS1 knockdown up-regulated genes related to the apoptosis pathway, including tumor necrosis factor superfamily 10 (TNFSF10), and sensitized prostate cancer cells to docetaxel treatment. Moreover, we also demonstrated that SOCS2-AS1 promotes androgen signaling by modulating the epigenetic control for AR target genes including TNFSF10. These findings suggest that SOCS2-AS1 plays an important role in the development of castration-resistant prostate cancer by repressing apoptosis.

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“…This suggests that some cell-free lncRNAs carry regulatory signals involved in pathological conditions such as tumor occurrence, invasion, and metastasis, and might thus be potential biomarkers for cancer [24-26]. Indeed, researchers have identified three circulating lncRNAs, Linc00152, CFLAR-AS1, and POU3F3, as potential biomarkers for predicting the development of human esophageal squamous cell carcinoma [27].…”

Section: Discussionmentioning

confidence: 99%

SCCA, TSGF, and the Long Non-Coding RNA AC007271.3 are Effective Biomarkers for Diagnosing Oral Squamous Cell Carcinoma

Shao¹,

Huang²,

Zheng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Oral squamous cell carcinoma (OSCC) is one of the most lethal malignancies worldwide and the most common type of oral cancer, characterized by invasive growth, frequent regional metastases, high recurrence, and poor prognosis. In the current study, we investigated the use of long non-coding RNAs (lncRNAs), tumor-specific growth factor (TSGF), and squamous cell carcinoma antigen (SCCA) as potential biomarkers for OSCC screening. Methods: LncRNA expression was measured by microarray analysis in three sets of OSCC and paired normal mucosal tissues. The potential lncRNAs involved in OSCC development were investigated by bioinformatics and verification experiments. We also determined the expression of these potential biomarkers in tissue and serum samples in a case–control study of 80 OSCC cases and 70 controls. Receiver operating characteristics, decision curve analysis, and the combined detection of lncRNA AC007271.3, TSGF, and SCCA were carried out to screen for OSCC biomarkers. Results: A total of 691 lncRNAs (433 upregulated and 258 downregulated) were differentially expressed in OSCC tissues compared with normal controls (p< 0.05). Based on Gene Ontology and pathway analysis, we selected four differentially expressed lncRNAs (AC007271.3, AC007182.6, LOC283481, and RP11-893F2.9), and showed that aberrant AC007271.3 levels in OSCC patients were significantly associated with clinical stage, especially in early-stage disease, in an expanded case–control study. The combination of AC007271.3 and SCCA (AUC=0.902, p< 0.001) showed significantly better ability to discriminate between OSCC and controls compared with SCCA or AC007271.3 alone. Serum AC007271.3, SCCA, and TSGF levels could also discriminate between OSCC and normal controls with sensitivities of 77.6%, 55.0%, and 63.3%, and specificities of 84.5%, 93.3%, and 66.7%, respectively. Conclusions: These results suggest that AC007271.3, SCCA, and TSGF could be novel circulating biomarkers for the determination of OSCC. However, further validation in large-scale prospective studies is necessary.

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LncRNA HOTAIR Enhances the Androgen-Receptor-Mediated Transcriptional Program and Drives Castration-Resistant Prostate Cancer

Cited by 296 publications

References 32 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

Androgen-induced Long Noncoding RNA (lncRNA) SOCS2-AS1 Promotes Cell Growth and Inhibits Apoptosis in Prostate Cancer Cells

SCCA, TSGF, and the Long Non-Coding RNA AC007271.3 are Effective Biomarkers for Diagnosing Oral Squamous Cell Carcinoma

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