Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB

Tripathi, Vidisha; Shen, Zhen; Chakraborty, Arindam; Giri, Sumanprava; Freier, Susan M.; Wu, Xiaolin; Zhang, Yongqing; Gorospe, Myriam; Prasanth, Supriya G.; Lal, Ashish; Prasanth, Kannanganattu V.

doi:10.1371/journal.pgen.1003368

Cited by 674 publications

(585 citation statements)

References 99 publications

(165 reference statements)

Supporting

Mentioning

557

Contrasting

Unclassified

Order By: Relevance

“…To this end, we used the https://www.ncbi.nlm.nih.gov/gds (GEO) to retrieve raw data sets (https://www.ncbi.nlm.nih.gov/sites/GDSbrowser/) in which normal human diploid fibroblasts (WI38) were depleted of MALAT1 18. Transcriptome analysis at the genome‐wide level was assessed by Illumina Human HT‐12 V4.0 expression beadchip.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, VEGFA was shown to be differentially down‐regulated after MALAT1 depletion (0.44‐fold decrease, nominal P = 0.0019, adjusted P = 0.02; GEO data set https://www.ncbi.nlm.nih.gov/sites/GDSbrowser/)18 (http://bio-annotation.cn/lncrna2target/). …”

Section: Resultsmentioning

confidence: 99%

“…Conversely, the progression into a more severe phenotype redirects the transcriptome toward pathways biologically related with mitochondrial dysfunction21, 22 and malignancy 4, 5, 10. In this respect, MALAT1 represents a remarkable functional and versatile molecule that modulates a myriad of signaling pathways, including cell cycle control,18 immune balance,23 and endothelial cell function and vessel growth 24. These phenomena, when present concurrently, escalate in complexity to entail cell proliferation and migration,25 apoptosis, fibrosis,26 and malignancy 27…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Metastasis‐associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune‐mediated liver damage

Sookoian

Flichman

Garaycoechea

et al. 2018

Hepatology Communications

View full text Add to dashboard Cite

Long noncoding RNAs (lncRNAs) are functional molecules that orchestrate gene expression. To identify lncRNAs involved in nonalcoholic fatty liver disease (NAFLD) severity, we performed a multiscale study that included: (a) systems biology modeling that indicated metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) as a candidate lncRNA for exploring disease‐related associations, (b) translational exploration in the clinical setting, and (c) mechanistic modeling. MALAT1 liver profiling was performed in three consecutive phases, including an exploratory stage (liver samples from patients with NAFLD who were morbidly obese [n = 47] and from 13 individuals with normal liver histology); a replication stage (patients with NAFLD and metabolic syndrome [n =49]); and a hypothesis‐driven stage (patients with chronic hepatitis C and autoimmune liver diseases, [n = 65]). Liver abundance of MALAT1 was associated with NAFLD severity (P = 1 × 10–6); MALAT1 expression levels were up‐regulated 1.75‐fold (P = 0.029) and 3.6‐fold (P = 0.012) in patients with nonalcoholic steatohepatitis compared to those diagnosed with simple steatosis (discovery and replication set, respectively; analysis of covariance adjusted by age, homeostasis model assessment, and body mass index). Quantification of liver vascular endothelial growth factor A messenger RNA, a target of MALAT1, revealed a significant correlation between the two RNAs (R, 0.58; P = 5 × 10–8). Increased levels of MALAT1 were also associated with autoimmune liver diseases. Interactome assessment uncovered significant biological pathways, including Janus kinase‐signal transducers and activators of transcription and response to interferon‐γ. Conclusion: Deregulated expression of MALAT1 stratifies patients into the histologic phenotypes associated with NAFLD severity. MALAT1 up‐regulation seems to be a common molecular mechanism in immune‐mediated chronic inflammatory liver damage. This suggests that convergent pathophenotypes (inflammation and fibrosis) share similar molecular mediators. (Hepatology Communications 2018;2:654‐665)

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Metastasis‐associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune‐mediated liver damage

Sookoian

Flichman

Garaycoechea

et al. 2018

Hepatology Communications

View full text Add to dashboard Cite

show abstract

“…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%

“…Differential expression of MALAT1 has been associated with G1/S and G2/M transitions of the cell cycle (25). Thus, we sought to understand the inference of miR338-5p/miR-421/MALAT1 axis in cell cycle regulation.…”

Section: Mir-338-5p and Mir-421 Regulate Oncogenic Long Non-coding Rnmentioning

confidence: 99%

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

Bhatia

Yadav

Tiwari

et al. 2018

Preprint

View full text Add to dashboard Cite

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.

show abstract

Noncoding RNAs in disease

2018

View full text Add to dashboard Cite

Noncoding RNAs are emerging as potent and multifunctional regulators in all biological processes. In parallel, a rapidly growing number of studies has unravelled associations between aberrant noncoding RNA expression and human diseases. These associations have been extensively reviewed, often with the focus on a particular microRNA (miRNA) (family) or a selected disease/pathology. In this Mini‐Review, we highlight a selection of studies in order to demonstrate the wide‐scale involvement of miRNAs and long noncoding RNAs in the pathophysiology of three types of diseases: cancer, cardiovascular and neurological disorders. This research is opening new avenues to novel therapeutic approaches.

show abstract

Long Noncoding RNA MALAT1 Controls Cell Cycle Progression by Regulating the Expression of Oncogenic Transcription Factor B-MYB

Cited by 674 publications

References 99 publications

Metastasis‐associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune‐mediated liver damage

Metastasis‐associated lung adenocarcinoma transcript 1 as a common molecular driver in the pathogenesis of nonalcoholic steatohepatitis and chronic immune‐mediated liver damage

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

Noncoding RNAs in disease

Contact Info

Product

Resources

About