<i>FIR</i>haplodeficiency promotes splicing to pyruvate kinase M2 in mice thymic lymphoma tissues revealed by six-plex tandem mass tag quantitative proteomic analysis

Kimura, Asako; Kïtamura, Kazuo; Ailiken, Guzhanuer; Satoh, Mamoru; Minamoto, Toshinari; Tanaka, Nobuko; Nomura, Fumio; Matsushita, Hiroshi

doi:10.18632/oncotarget.19061

Cited by 9 publications

(10 citation statements)

References 26 publications

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“…Additionally, FIR deficiency promoted alternative splicing to increase pyruvate kinase M2 that engages in the glucose metabolism of cancers in mice thymic lymphoma tissues 44 . Moreover, the long non-coding RNAs (lncRNAs) are a novel class of regulatory genes that have critical roles in cancer progression, and translational regulatory lncRNA (treRNA) downregulates the expression of the epithelial marker E-cadherin by suppressing the translation of its mRNA 45 .…”

Section: Discussionmentioning

confidence: 99%

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

et al. 2020

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Brahma-related gene 1 (BRG1), an ATPase subunit of the SWItch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex controls multipotent neural crest formation by regulating epithelial-mesenchymal transition (EMT)-related genes with adenosine triphosphate-dependent chromodomain-helicase DNA-binding protein 7 (CHD7). The expression of BRG1 engages in pre-mRNA splicing through interacting RNPs in cancers; however, the detailed molecular pathology of how BRG1and CHD7 relate to cancer development remains largely unveiled. This study demonstrated novel post-transcriptional regulation of BRG1 in EMT and relationship with FIRΔexon2, which is a splicing variant of the far-upstream element-binding protein (FUBP) 1-interacting repressor (FIR) lacking exon 2, which fails to repress c-myc transcription in cancers. Previously, we have reported that FIR complete knockout mice (FIR −/− ) was embryonic lethal before E9.5, suggesting FIR is crucial for development. FIRΔexon2 acetylated H3K27 on promoter of BRG1 by CHIP-sequence and suppressed BRG1 expression post-transcriptionally; herein BRG1 suppressed Snai1 that is a transcriptional suppressor of E-cadherin that prevents cancer invasion and metastasis. Ribosomal proteins, hnRNPs, splicing-related factors, poly (A) binding proteins, mRNA-binding proteins, tRNA, DEAD box, and WD-repeat proteins were identified as co-immunoprecipitated proteins with FIR and FIRΔexon2 by redoing exhaustive mass spectrometry analysis. Furthermore, the effect of FIRΔexon2 on FGF8 mRNA splicing was examined as an indicator of neural development due to impaired CHD7 revealed in CHARGE syndrome. Expectedly, siRNA of FIRΔexon2 altered FGF8 pre-mRNA splicing, indicated close molecular interaction among FIRΔexon2, BRG1 and CHD7. FIRΔexon2 mRNA was elevated in human gastric cancers but not in non-invasive gastric tumors in FIR +/ mice (K19-Wnt1/C2mE x FIR +/− ). The levels of FIR family (FIR, FIRΔexon2 and PUF60), BRG1, Snai1, FBW7, E-cadherin, c-Myc, cyclin-E, and SAP155 increased in the gastric tumors in FIR +/− mice compared to those expressed in wild-type mice. FIR family, Snai1, cyclin-E, BRG1, and c-Myc showed trends toward higher expression in larger tumors than in smaller tumors in Gan-mice (K19-Wnt1/C2mE). The expressions of BRG1 and Snai1 were positively correlated in the gastric tumors of the Gan-mice. Finally, BRG1 is a candidate substrate of F-box and WD-repeat domain-containing 7 (FBW7) revealed by three-dimensional crystal structure analysis that the U2AF-homology motif (UHM) of FIRΔexon2 interacted with tryptophan-425 and asparate-399 (WD)-like motif in the degron pocket of FBW7 as a UHM-ligand motif. Together, FIRΔexon2 engages in multi-step post-transcriptional regulation of BRG1, affecting EMT through the BRG1/Snai1/E-cadherin pathway and promoting tumor proliferation and invasion of gastric cancers.

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Section: Discussionmentioning

confidence: 99%

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

et al. 2020

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“…The impact of EDNRB silencing on the protein expression profiles of the cells was determined by tandem mass tag–based spectrometry . Briefly, MDA‐MB‐231/EDNRBsh and control MDA‐MB‐231/NC cells were harvested and their proteins were extracted.…”

Section: Methodsmentioning

confidence: 99%

Knockdown of endothelin receptor B inhibits the progression of triple‐negative breast cancer

Han

Cui

et al. 2019

Annals of the New York Academy of Sciences

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Endothelin receptor B (EDNRB) is one of the receptors in the endothelin axis and its upregulated expression is associated with tumorigenesis and metastasis of several types of solid tumors. However, the expression profile of EDNRB in breast cancer and its role in the progression of breast cancer are unclear. Here, we show that EDNRB expression is higher in metastatic tumors than in primary breast cancer, and is associated significantly with lymph node metastasis and poor survival in Chinese patients with breast cancer. EDNRB expression was particularly upregulated in triple‐negative breast cancer (TNBC) cells. Moreover, EDNRB silencing by a specific shRNA significantly attenuated the proliferation, migration, and invasiveness of MDA‐MB‐231 and BT549 cells and increased their apoptosis, as well as retarded the growth of implanted tumors in mice. Tandem mass spectrometry analysis indicated that 248 proteins were differentially expressed in EDNRB‐silenced cells and their cellular organelles, and these proteins participate in many processes. EDNRB silencing decreased protein kinase B and extracellular regulated protein kinase phosphorylation and promoted the mesenchymal‐to‐epithelial transition process in MDA‐MB‐231 cells. Therefore, our findings provide strong evidence for the first time that knockdown of EDNRB expression inhibits the progression of TNBC and that EDNRB can serve as a prognostic biomarker and therapeutic target for the treatment of TNBC.

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“…Accordingly, the interaction of FIR/FIRΔexon2 bridges c-Myc and P27Kip1 expression [ 4 ]. Fascinatingly, FIR haplodeficiency promotes splicing to pyruvate kinase M2 in mice thymic lymphoma tissues, indicating disturbed splicing of FIR or a dominant negative form of FIR interferes cancer metabolism [ 34 ]. Adenovirus vector–mediated FIR expressions enhanced the efficacy of heavy particle beam on the subcutaneously xenografted esophageal cancer cells into the thigh of nude mice (BALB/c), indicating increased DNA damage or delayed DNA damage repair [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Disturbed alternative splicing of FIR (PUF60) directed cyclin E overexpression in esophageal cancers

et al. 2018

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Overexpression of alternative splicing of far upstream element binding protein 1 (FUBP1) interacting repressor (FIR; poly(U) binding splicing factor 60 [PUF60]) and cyclin E were detected in esophageal squamous cell carcinomas (ESCC). Accordingly, the expression of FBW7 was examined by which cyclin E is degraded as a substrate via the proteasome system. Expectedly, FBW7 expression was decreased significantly in ESCC. Conversely, c-myc gene transcriptional repressor FIR (alias PUF60; U2AF-related protein) and its alternative splicing variant form (FIRΔexon2) were overexpressed in ESCC. Further, anticancer drugs (cis-diaminedichloroplatinum/cisplatin [CDDP] or 5-fluorouracil [5-FU]) and knockdown of FIR by small interfering RNA (siRNA) increased cyclin E while knockdown of FIRΔexon2 by siRNA decreased cyclin E expression in ESCC cell lines (TE1, TE2, and T.Tn) or cervical SCC cells (HeLa cells). Especially, knockdown of SAP155 (SF3b1), a splicing factor required for proper alternative splicing of FIR pre-mRNA, decreased cyclin E. Therefore, disturbed alternative splicing of FIR generated FIR/FIRΔexon2 with cyclin E overexpression in esophageal cancers, indicating that SAP155 siRNA potentially rescued FBW7 function by reducing expression of FIR and/or FIRΔexon2. Remarkably, Three-dimensional structure analysis revealed the hypothetical inhibitory mechanism of FBW7 function by FIR/FIRΔexon2, a novel mechanism of cyclin E overexpression by FIR/FIRΔexon2-FBW7 interaction was discussed. Clinically, elevated FIR expression potentially is an indicator of the number of lymph metastases and anti-FIR/FIRΔexon2 antibodies in sera as cancer diagnosis, indicating chemical inhibitors of FIR/FIRΔexon2-FBW7 interaction could be potential candidate drugs for cancer therapy. In conclusion, elevated cyclin E expression was, in part, induced owing to potential FIR/FIRΔexon2–FBW7 interaction in ESCC.

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FIRhaplodeficiency promotes splicing to pyruvate kinase M2 in mice thymic lymphoma tissues revealed by six-plex tandem mass tag quantitative proteomic analysis

Cited by 9 publications

References 26 publications

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer

Knockdown of endothelin receptor B inhibits the progression of triple‐negative breast cancer

Disturbed alternative splicing of FIR (PUF60) directed cyclin E overexpression in esophageal cancers

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