Pituitary adenylate cyclase-activating polypeptide is regulated by alternative splicing of transcriptional repressor REST/NRSF in nerve injury

Shudo, Yoshie; Shimojo, Masahito; Fukunaga, Mikihiko; Ito, Seiji

doi:10.1016/j.lfs.2015.10.033

Cited by 8 publications

(7 citation statements)

References 47 publications

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“…The single band corresponding each Flag-tagged REST or Flagtagged sREST without any non-specific bands were appeared confirming the specific expression of each protein. Although data that empty plasmid was not shown for immunoblot, no expression was confirmed even in previous report [25]. After transfection of each plasmid, cell viability of SCLC by the expression of REST, but not sREST, decreased significantly compared to that of the empty plasmid (Fig.…”

Section: Exogenous Reconstitution Of Rest In Sclc Cellssupporting

confidence: 61%

“…Thus, we analyzed the effect of the exogenous reconstitution of REST in H146 SCLC cells. Flag-tagged REST and Flag-tagged sREST were previously constructed using pCMV-Tag2 vector [ 25 ]. Each Flag-tagged expression plasmid was transfected in H146 cells cultured for 24 h and cell lysates were analyzed for each expression by western blot analysis (Fig.…”

Section: Resultsmentioning

confidence: 99%

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An antisense amido-bridged nucleic acid gapmer oligonucleotide targeting SRRM4 alters REST splicing and exhibits anti-tumor effects in small cell lung cancer and prostate cancer cells

et al. 2023

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Background Antisense oligonucleotide (ASO) medicine for clinical applications has been becoming a reality. We previously developed a gapmer ASO targeting Ser/Arg repetitive matrix 4 (SRRM4) that is abnormally expressed in small cell lung cancer (SCLC). However the detailed mechanism of ASO through repressing SRRM4 has not been completely elucidated. Further, effectiveness of SRRM4 ASO to prostate cancer (PCa) cells expressing SRRM4 similar to SCLC remains to be elucidated. RE1-silencing transcription factor (REST) is a tumor suppressor, and its splicing isoform (sREST) is abnormally expressed by SRRM4 and causes carcinogenesis with neuroendocrine phenotype in SCLC. The present study aimed to understand the contribution of REST splicing by SRRM4 ASO administration. Methods SRRM4 expression and REST splicing were analyzed by RT-qPCR and conventional RT-PCR after treating SRRM4 ASO, and cell viability was analyzed in vitro. Exogenous reconstitution of Flag-tagged REST plasmid in SCLC cells and the splice-switching oligonucleotide (SSO) specific for REST was analyzed for cell viability. Furthermore, we expanded the application of SRRM4 ASO in PCa cells abnormally expressing SRRM4 mRNA in vitro. Results SRRM4 ASO successfully downregulated SRRM4 expression, followed by repressed cell viability of SCLC and PCa cells in a dose-dependent manner. Administration of SRRM4 ASO then modified the alternative splicing of REST, resulting reduced cell viability. REST SSO specifically modified REST splicing increased REST expression, resulting in reduced cell viability. Conclusions Our data demonstrate that a gapmer ASO targeting SRRM4 (SRRM4 ASO) reduces cell viability through splicing changes of REST, followed by affecting REST-controlled genes in recalcitrant tumors SCLC and PCa cells.

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Section: Exogenous Reconstitution Of Rest In Sclc Cellssupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

An antisense amido-bridged nucleic acid gapmer oligonucleotide targeting SRRM4 alters REST splicing and exhibits anti-tumor effects in small cell lung cancer and prostate cancer cells

et al. 2023

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“…REST is a key target oncogenic transformation and neural differentiation and inhibits transcription by regulating chromatin structure or inhibiting underlying transcription mechanisms [25][26][27]. During neuron development, REST is the main transcriptional repressor of neuronspecific genes and plays an important role in nonneuron and neuronal progenitor cells through histone deacetylation, chromatin remodeling, methylation, and other mechanisms [28][29][30][31]. Recent studies have confirmed that REST is closely related to carcinogenesis and cancer progression [32].…”

Section: Discussionmentioning

confidence: 99%

Low REST Expression Indicates a Biomarker of Poor Prognosis in Patients with Renal Cell Carcinoma

Zhang

et al. 2021

BioMed Research International

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It was initially found that neural-restrictive silencer factor/repressor 1-silencing transcription factor (REST) is a transcriptional repressor of neuronal genes in nonneuronal cells. However, it is reported to be abundantly expressed in various types of aggressive cancer cells. In this study, we evaluated the expression patterns of REST in renal cell carcinoma and found that its expression is lower in tumor tissues compared to normal tissues. The chi-square test showed that the low REST expression was closely related to patients’ clinicopathologic parameters, including the pathologic stage and survival status. ROC curve showed that REST had excellent clinical diagnostic prospect. In addition, patients with low REST expression had poor over survival (OS) and relapse-free survival (RFS). Univariate and multivariate Cox regression analysis confirmed that the low REST expression was an independent predictor of poor prognosis in renal cell carcinoma. Gene set enrichment analysis identified P53 pathway, reactive oxygen species pathway, glycolysis, DNA repair, cholesterol homeostasis, and MYC targets V2 enriched with low REST expression phenotype. These results suggested that REST may be a novel biomarker for the diagnosis and prognosis of renal cell carcinoma in clinical applications.

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“…Last, since this study is a fixed-point observation one week after peripheral nerve injury, it only evaluates the effect of peripheral nerve injury and aging in a limited manner. It has been reported that the expression of nerve-specific proteins varies greatly depending on the time after nerve injury (9,(48)(49)(50)(51). We believe that it may be possible to evaluate the effect of peripheral nerve injury and aging in more detail by evaluating with time course.…”

Section: Discussionmentioning

confidence: 93%

Age‑related differences for expression of the nerve‑specific proteins after peripheral nerve injury

et al. 2022

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Pituitary adenylate cyclase-activating polypeptide is regulated by alternative splicing of transcriptional repressor REST/NRSF in nerve injury

Cited by 8 publications

References 47 publications

An antisense amido-bridged nucleic acid gapmer oligonucleotide targeting SRRM4 alters REST splicing and exhibits anti-tumor effects in small cell lung cancer and prostate cancer cells

An antisense amido-bridged nucleic acid gapmer oligonucleotide targeting SRRM4 alters REST splicing and exhibits anti-tumor effects in small cell lung cancer and prostate cancer cells

Low REST Expression Indicates a Biomarker of Poor Prognosis in Patients with Renal Cell Carcinoma

Age‑related differences for expression of the nerve‑specific proteins after peripheral nerve injury

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