Sam68 binds Alu-rich introns in SMN and promotes pre-mRNA circularization

Pagliarini, Vittoria; Jolly, Ariane; Bielli, Pamela; Rosa, Valentina Di; Grange, Pierre de la; Sette, Claudio

doi:10.1093/nar/gkz1117

Cited by 56 publications

(57 citation statements)

References 45 publications

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“…After a series of experiments, we con rmed the molecular mechanism that SRSF7 promoted the formation and expression level of circ-PLEKHA5 through binding to PLEKHA5 pre-mRNA. Similar to our nding, RBP-Sam68 has been reported to promote the circularization of SMN exons along with the generation of circ-SMN by binding to SMN pre-mRNA [34] . RBP-QKI binds to the upstream and downstream of SMARCA5 pre-mRNA anking sequence and promotes the cyclization of adjacent exons to form circ-SMARCA5 [31] .…”

Section: Discussionsupporting

confidence: 90%

Biosynthetic circ-PLEKHA5 stabilized by SRSF7 promotes the vasculogenic mimicry of glioblastoma cells by encoding a novel protein 622aa

Su¹,

Liu

Teng

et al. 2020

Preprint

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Background: Increasing studies have been demonstrated that circRNAs play vital regulatory roles in the biological behaviors of glioblastoma cells, and increasing circRNAs are found to have the capacity of encoding small peptides, which are involved in the regulatory process.Methods: Western blot and qRT-PCR were conducted to confirm the expression of SRSF7 and circ-PLEKHA5 respectively. RNase R digestion assay and fluorescence in situ hybridization assays were conducted to evaluate the existence and cellular location of circ-PLEKHA5. RIP assay was used to access the relationship between SRSF7 and circ-PLEKHA5. Dual-luciferase assay and FLAG tag assays were performed to test the coding capability of circ-PLEKHA5. Immunofluorescence assay was conducted to evaluate the location of circ-PLEKHA5-622aa. CCK-8, vasculogenic mimicry (VM) formation and transwell assays were used to evaluate the roles of SRSF7, circ-PLEKHA5, circ-PLEKHA5-622aa on proliferation, VM formation, migration and invasion. Nude mice xenograft studys with PAS-CD34 staining were used to clarify the functional roles of SRSF7 and circ-PLEKHA5 on VM formation in vivo.Results: SRSF7 was up-regulated in glioma, and promoted the proliferation, migration, invasion, VM formation and the expression of VM-associated proteins of glioma cells by increasing the expression of circ-PLEKHA5. Circ-PLEKHA5 was mainly localized in cytoplasm and promoted the proliferation, migration, invasion, VM formation and the expression of VM-associated proteins of glioma cells by encoding a novel protein circ-PLEKHA5-622aa. The application of SRSF7 and circ-PLEKHA5 inhibitor significantly suppressed the tumor growth and VM formation in vivo.Conclusions: This study first demonstrated the coding ability of circ-PLEKHA5, and identified the regulatory roles of SRSF7/circ-PLEKHA5/circ-PLEKHA5-622aa pathway in VM formation of glioblastoma cells. Our findings might provide a novel strategy for glioma treatment.

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Section: Discussionsupporting

confidence: 90%

Biosynthetic circ-PLEKHA5 stabilized by SRSF7 promotes the vasculogenic mimicry of glioblastoma cells by encoding a novel protein 622aa

Su¹,

Liu

Teng

et al. 2020

Preprint

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“…According to results of previous studies, the CLIP analysis was performed 41 , 42 . After irradiated on ice (100 mJ/cm 2 ), treated cells were lysed using lysis buffer (50 mM Tris, pH 8.0, 100 mM NaCl, 1 mM MgCl 2 , 0.5 mM Na 3 VO 4 , 0.1 mM CaCl 2 , 1% NP-40, 1 mM DTT, RNase inhibitor (Takara, 2313A), and protease inhibitor cocktail (Roche, 5892970001).…”

Section: Methodsmentioning

confidence: 99%

SAM68 promotes tumorigenesis in lung adenocarcinoma by regulating metabolic conversion via PKM alternative splicing

Zhu¹,

Chen²,

Wang³

et al. 2021

Theranostics

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Background: A metabolic “switch” from oxidative phosphorylation to glycolysis provides tumor cells with energy and biosynthetic substrates, thereby promoting tumorigenesis and malignant progression. However, the mechanisms controlling this metabolic switch in tumors is not entirely clear. Methods: Clinical specimens were used to determine the effect of SAM68 on lung adenocarcinoma (LUAD) tumorigenesis and metastasis, and mouse models and molecular biology assays were performed to elucidate the function and underlying mechanisms in vitro and in vivo . Results: SAM68 mRNA levels were higher in LUAD tissue than in normal lung tissue, indicating that SAM68 expression is upregulated in LUAD. Patients with LUAD with SAM68 high (n = 257) had a higher frequency of tumor recurrence ( p = 0.025) and recurrence-free survival ( p = 0.013) than did those with SAM68 low (n = 257). Patients with SAM68 high mRNA levels (n = 257) were at a higher risk for cancer-related death ( p = 0.006), and had shorter overall survival ( p = 0.044) than did those with SAM68 low . SAM68 promotes tumorigenesis and metastasis of LUAD cells in vitro and in vivo by regulating the cancer metabolic switch. SAM68 drives cancer metabolism by mediating alternative splicing of pyruvate kinase (PKM) pre-mRNAs, and promoting the formation of PKM2. Mechanistically, SAM68 increased the binding of the splicing repressor hnRNP A1 to exon 9 of PKM , thereby enhancing PKM2 isoform formation and PKM2-dependent aerobic glycolysis and tumorigenesis. Conclusions: SAM68 promotes LUAD cell tumorigenesis and cancer metabolic programming via binding of the 351-443 aa region of SAM68 to the RGG motif of hnRNP A1, driving hnRNP A1-dependent PKM splicing, contributing to increased oncogene PKM2 isoform formation and inhibition of PKM1 isoform formation. SAM68 is therefore a promising therapeutic target for the treatment of LUAD.

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“…It is worth to mention that knocking-down of HNRNPL not only resulted in the reduction of circFAM73A, but also caused a slight increase of FAM73A. A recent study also reported that interfering with SMN circRNAs biogenesis leads to the signi cant rescue of SMN protein [49], implicating the competition between canonical splicing and back-splicing, when back-splicing of exons for circRNA formation is considered as an unusual type of alternative splicing. This competition might explain the increase of linear FAM73A mRNA caused by HNRNPL depletion as it impedes the back-splicing of pre-FAM73A.…”

Section: Discussionmentioning

confidence: 95%

circFAM73A Promotes Cancer Stem Cell-like Properties of Gastric Cancer Through miR-490-3p/HMGA2 Positive Feedback and HNRNPK-mediated β-catenin Stabilization.

Xia

Jiang

et al. 2020

Preprint

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Background: Circular RNAs (circRNAs) have emerged as a new subclass of regulatory RNAs that exert critical roles in various cancers. Cancer stem cells (CSCs), a small subset of cancer cells, are believed to possess the capacities to initiate tumorigenesis and promote progression. Although accumulating evidences have suggested that cells with CSC-like properties are crucial for the malignance process of gastric cancer (GC), it remains inexplicit whether circRNAs are interrelated with the acquisition of CSC-like properties in GC.Methods: circFAM73A expression was analyzed by GEO datasets and verified in GC samples. The role of circFAM73A on GC cell proliferation, migration, cisplatin resistance and CSC-like properties were determined by a series of functional experiment both in vitro and in vivo. RNA pull down was used to explore the miRNAs and proteins binding to circFAM73A. Bioinformatic analysis and experimental verification confirmed the downstream of circFAM73A. The regulation of HMGA2 on circFAM73A was verified by ChIP and RIP assays.Results: Elevated circFAM73A expression was confirmed in GC tissues and higher circFAM73A predicts poor prognosis of GC patients. The upregulation of circFAM73A enhanced CSC-like properties in GC, thus, exerting the facilitating role on cell proliferation, migration and cisplatin resistance. Mechanistically, circFAM73A promoted GC malignancy by regulating miR-490-3p/HMGA2 in a positive feedback loop and recruiting HNRNPK to facilitate β-catenin stabilization. Moreover, HMGA2 further enhanced E2F1 and HNRNPL activity, which in turn promotes circFAM73A expression.Conclusions: Our work demonstrates the crucial role of circFAM73A on GC CSC-like properties and uncovers a positive feedback loop on circFAM73A regulation that leads to the progression of gastric cancer, which may provide a new insight for circRNA-based diagnostic and therapeutic strategies.

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Sam68 binds Alu-rich introns in SMN and promotes pre-mRNA circularization

Cited by 56 publications

References 45 publications

Biosynthetic circ-PLEKHA5 stabilized by SRSF7 promotes the vasculogenic mimicry of glioblastoma cells by encoding a novel protein 622aa

Biosynthetic circ-PLEKHA5 stabilized by SRSF7 promotes the vasculogenic mimicry of glioblastoma cells by encoding a novel protein 622aa

SAM68 promotes tumorigenesis in lung adenocarcinoma by regulating metabolic conversion via PKM alternative splicing

circFAM73A Promotes Cancer Stem Cell-like Properties of Gastric Cancer Through miR-490-3p/HMGA2 Positive Feedback and HNRNPK-mediated β-catenin Stabilization.

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Sam68 binds Alu-rich introns in SMN and promotes pre-mRNA circularization

Cited by 56 publications

References 45 publications

Biosynthetic circ-PLEKHA5 stabilized by SRSF7 promotes the vasculogenic mimicry of glioblastoma cells by encoding a novel protein 622aa

Biosynthetic circ-PLEKHA5 stabilized by SRSF7 promotes the vasculogenic mimicry of glioblastoma cells by encoding a novel protein 622aa

SAM68 promotes tumorigenesis in lung adenocarcinoma by regulating metabolic conversion via PKM alternative splicing

circFAM73A&nbsp;Promotes Cancer Stem Cell-like Properties of Gastric Cancer Through miR-490-3p/HMGA2&nbsp;Positive Feedback and HNRNPK-mediated β-catenin Stabilization.

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circFAM73A Promotes Cancer Stem Cell-like Properties of Gastric Cancer Through miR-490-3p/HMGA2 Positive Feedback and HNRNPK-mediated β-catenin Stabilization.