RNA splicing factor USP39 promotes glioma progression by inducing TAZ mRNA maturation

Ding, Kaikai; Ji, Jianxiong; Zhang, Xin; Huang, Bin; Chen, Anjing; Zhang, Di; Li, Xingang; Wang, Xinyu; Wang, Jian

doi:10.1038/s41388-019-0888-1

Cited by 41 publications

(39 citation statements)

References 46 publications

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“…The decreased levels of LATS1 unleash YAP activity and support pro-oncogenic features in glioma cells [74] (Table 2). In line with these observations, the splicing factor USP39 is up-regulated in high-grade gliomas [73], whereas reduced levels of LATS1 associate with poor prognosis in glioma patients [75]. Although the mechanisms driving these splicing-related events (i.e., up-regulation of USP39 and splicing of PMEPA1a) are still unknown, these studies suggest that splicing dysregulation impacts a key developmental program by altering the equilibrium of the Hippo pathway during gliomagenesis.…”

Section: Hippo Signaling Pathwaysupporting

confidence: 52%

“…Splicing factors can impact the expression of components of the Hippo pathway in brain tumors. For instance, the ubiquitin specific protease 39 (USP39), promotes RNA processing and expression of TAZ, thus favoring glioma oncogenic features in vitro and in vivo [73] (Table 2). Furthermore, recent evidence indicates that gliomas express high levels of a splice variant of the prostate transmembrane (TM) protein, androgen induced 1 (PMEPA1) called PMEPA1a, which promotes degradation of the tumor suppressor LATS1 protein.…”

Section: Hippo Signaling Pathwaymentioning

confidence: 99%

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Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Bielli

Pagliarini

Pieraccioli

et al. 2019

Cells

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Brain tumors are a heterogeneous group of neoplasms ranging from almost benign to highly aggressive phenotypes. The malignancy of these tumors mostly relies on gene expression reprogramming, which is frequently accompanied by the aberrant regulation of RNA processing mechanisms. In brain tumors, defects in alternative splicing result either from the dysregulation of expression and activity of splicing factors, or from mutations in the genes encoding splicing machinery components. Aberrant splicing regulation can generate dysfunctional proteins that lead to modification of fundamental physiological cellular processes, thus contributing to the development or progression of brain tumors. Herein, we summarize the current knowledge on splicing abnormalities in brain tumors and how these alterations contribute to the disease by sustaining proliferative signaling, escaping growth suppressors, or establishing a tumor microenvironment that fosters angiogenesis and intercellular communications. Lastly, we review recent efforts aimed at developing novel splicing-targeted cancer therapies, which employ oligonucleotide-based approaches or chemical modulators of alternative splicing that elicit an impact on brain tumor biology.

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Section: Hippo Signaling Pathwaysupporting

confidence: 52%

Section: Hippo Signaling Pathwaymentioning

confidence: 99%

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Bielli

Pagliarini

Pieraccioli

et al. 2019

Cells

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“…Previous studies have shown that attenuation in splicing factor-driven RNA maturation promotes tumorigenesis through the accumulation of pre-mRNAs 51,52 . We found decreased expression of KSR2 due to impairment in SF3B1-mediated mRNA maturation and KSR2 partially contributes to SF3B1 pro-proliferative function.…”

Section: Discussionmentioning

confidence: 99%

Splicing factor SF3B1 promotes endometrial cancer progression via regulating KSR2 RNA maturation

Popli¹,

Richters

Chadchan³

et al. 2020

Cell Death Dis

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Although endometrial cancer is the most common cancer of the female reproductive tract, we have little understanding of what controls endometrial cancer beyond the transcriptional effects of steroid hormones such as estrogen. As a result, we have limited therapeutic options for the ~62,000 women diagnosed with endometrial cancer each year in the United States. Here, in an attempt to identify new prognostic and therapeutic targets, we focused on a new area for this cancer—alternative mRNA splicing—and investigated whether splicing factor, SF3B1, plays an important role in endometrial cancer pathogenesis. Using a tissue microarray, we found that human endometrial tumors expressed more SF3B1 protein than non-cancerous tissues. Furthermore, SF3B1 knockdown reduced in vitro proliferation, migration, and invasion of the endometrial cancer cell lines Ishikawa and AN3CA. Similarly, the SF3B1 inhibitor, Pladienolide-B (PLAD-B), reduced the Ishikawa and AN3CA cell proliferation and invasion in vitro. Moreover, PLAD-B reduced tumor growth in an orthotopic endometrial cancer mouse model. Using RNA-Seq approach, we identified ~2000 differentially expressed genes (DEGs) with SF3B1 knockdown in endometrial cancer cells. Additionally, alternative splicing (AS) events analysis revealed that SF3B1 depletion led to alteration in multiple categories of AS events including alternative exon skipping (ES), transcript start site usage (TSS), and transcript termination site (TTS) usage. Subsequently, bioinformatics analysis showed KSR2 as a potential candidate for SF3B1-mediated functions in endometrial cancer. Specifically, loss of SF3B1 led to decrease in KSR2 expression, owing to reduced maturation of KSR2 pre-mRNA to a mature RNA. Importantly, we found rescuing the KSR2 expression with SF3B1 knockdown partially restored the cell growth of endometrial cancer cells. Taken together, our data suggest that SF3B1 plays a crucial oncogenic role in the tumorigenesis of endometrial cancer and hence may support the development of SF3B1 inhibitors to treat this disease.

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“…The 10 hub genes expressed in lung cancer analyzed by Oncomine. To investigate the clinical significance of the hub genes, the expression of these 10 hub genes in lung cancer and normal tissues was analyzed with the Oncomine database 26,50,51 . A previous study (Bhattacharjee) 52 revealed that EGFR mRNA expression levels were significantly higher in squamous cell lung carcinoma than in lung (Fig.…”

Section: Survival Analysis Of Hub Genesmentioning

confidence: 99%

Cellular processes involved in lung cancer cells exposed to direct current electric field

Liu

Yang

et al. 2020

Sci Rep

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With the rapid breakthrough of electrochemical treatment of tumors, electric field (EF)-sensitive genes, previously rarely exploited, have become an emerging field recently. Here, we reported our work for the identification of EF-sensitive genes in lung cancer cells. The gene expression profile (GSE33845), in which the human lung cancer CL1-0 cells were treated with a direct current electric field (dcEF) (300 mV/mm) for 2 h, was retrieved from GEO database. Differentially expressed genes (DEGs) were acquired, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) and protein-protein interaction (PPI) analysis. Hub genes were acquired and analyzed by various tools including the Human Protein Atlas, Kaplan-Meier analysis, Cytoscape, FunRich, Oncomine and cBioPortal. Subsequently, three-dimensional protein models of hub genes were modeled by Modeller 9.20 and Rosetta 3.9. Finally, a 100 ns molecular dynamics simulation for each hub protein was performed with GROMACS 2018.2. A total of 257 DEGs were acquired and analyzed by GO, KEGG and PPI. Then, 10 hub genes were obtained, and the signal pathway analysis showed that two inflammatory pathways were activated: the FoxO signaling pathway and the AGE-RAGE signaling pathway. The molecular dynamic analysis including RMSD and the radius of gyration hinted that the 3D structures of hub proteins were built. Overall, our work identified EF-sensitive genes in lung cancer cells and identified that the inflammatory state of tumor cells may be involved in the feedback mechanism of lung cancer cells in response to electric field stimulation. In addition, qualified three-dimensional protein models of hub genes were also constructed, which will be helpful in understanding the complex effects of dcEF on human lung cancer CL1-0 cells.

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RNA splicing factor USP39 promotes glioma progression by inducing TAZ mRNA maturation

Cited by 41 publications

References 46 publications

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Splicing factor SF3B1 promotes endometrial cancer progression via regulating KSR2 RNA maturation

Cellular processes involved in lung cancer cells exposed to direct current electric field

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