The oncogenic RNA-binding protein SRSF1 regulates LIG1 in non-small cell lung cancer

Martínez-Terroba, Elena; Ezponda, Teresa; Bértolo, Cristina; Sainz, Cristina; Remírez, Ana; Agorreta, Jackeline; Garmendia, Irati; Behrens, Carmen; Pı́o, Rubén; Wistuba, Ignacio I.; Montuenga, Luis M.; Pajares, María J.

doi:10.1038/s41374-018-0128-2

Cited by 33 publications

(15 citation statements)

References 38 publications

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“…Here, we validate, through RIP data, the physical interaction between circSMARCA5 and SRSF1 in human GBM cells. SRSF1 is a protein involved in many biomolecular functions [20] and its expression is known to be upregulated in several cancers [30,31]. In order to understand if the interaction between circSMARCA5 and SRSF1 may alter the splicing pattern of SRSF1’s targets, we focused on VEGFA.…”

Section: Discussionmentioning

confidence: 99%

CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1

Barbagallo

Caponnetto

Brex

et al. 2019

Cancers

145

183

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Circular RNAs are a large group of RNAs whose cellular functions are still being investigated. We recently proposed that circSMARCA5 acts as sponge for the splicing factor Serine and Arginine Rich Splicing Factor 1 (SRSF1) in glioblastoma multiforme (GBM). After demonstrating by RNA immunoprecipitation a physical interaction between SRFS1 and circSMARCA5, we assayed by real-time PCR in a cohort of 31 GBM biopsies and 20 unaffected brain parenchyma controls (UC) the expression of total, pro-angiogenic (Iso8a) and anti-angiogenic (Iso8b) mRNA isoforms of Vascular Endothelial Growth Factor A (VEGFA), a known splicing target of SRSF1. The Iso8a to Iso8b ratio: (i) increased in GBM biopsies with respect to UC (p-value < 0.00001); (ii) negatively correlated with the expression of circSMARCA5 (r-value = −0.46, p-value = 0.006); (iii) decreased in U87-MG overexpressing circSMARCA5 with respect to negative control (p-value = 0.0055). Blood vascular microvessel density, estimated within the same biopsies, negatively correlated with the expression of circSMARCA5 (r-value = −0.59, p-value = 0.00001), while positively correlated with that of SRSF1 (r-value = 0.38, p-value = 0.00663) and the Iso8a to Iso8b ratio (r-value = 0.41, p-value = 0.0259). Kaplan-Meier survival analysis showed that GBM patients with low circSMARCA5 expression had lower overall and progression free survival rates than those with higher circSMARCA5 expression (p-values = 0.033, 0.012, respectively). Our data convincingly suggest that circSMARCA5 is an upstream regulator of pro- to anti-angiogenic VEGFA isoforms ratio within GBM cells and a highly promising GBM prognostic and prospective anti-angiogenic molecule.

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Section: Discussionmentioning

confidence: 99%

CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1

Barbagallo

Caponnetto

Brex

et al. 2019

Cancers

145

183

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“…SRSF1 as a classic member of the SR protein family, has been reported in several cancers and is associated with poor prognosis [22,41]. Moreover, cardinal studies have shown that SRSF1 is upregulated in several tumors and exerts tumorigenesis roles by regulating the AS events of some cancer-related genes [42][43][44]. However, the clinical significance and biological function of SRSF1 in BRCA remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1

Luo

Zhang

et al. 2021

J Exp Clin Cancer Res

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Background Intensive evidence has highlighted the effect of aberrant alternative splicing (AS) events on cancer progression when triggered by dysregulation of the SR protein family. Nonetheless, the underlying mechanism in breast cancer (BRCA) remains elusive. Here we sought to explore the molecular function of SRSF1 and identify the key AS events regulated by SRSF1 in BRCA. Methods We conducted a comprehensive analysis of the expression and clinical correlation of SRSF1 in BRCA based on the TCGA dataset, Metabric database and clinical tissue samples. Functional analysis of SRSF1 in BRCA was conducted in vitro and in vivo. SRSF1-mediated AS events and their binding motifs were identified by RNA-seq, RNA immunoprecipitation-PCR (RIP-PCR) and in vivo crosslinking followed by immunoprecipitation (CLIP), which was further validated by the minigene reporter assay. PTPMT1 exon 3 (E3) AS was identified to partially mediate the oncogenic role of SRSF1 by the P-AKT/C-MYC axis. Finally, the expression and clinical significance of these AS events were validated in clinical samples and using the TCGA database. Results SRSF1 expression was consistently upregulated in BRCA samples, positively associated with tumor grade and the Ki-67 index, and correlated with poor prognosis in a hormone receptor-positive (HR+) cohort, which facilitated proliferation, cell migration and inhibited apoptosis in vitro and in vivo. We identified SRSF1-mediated AS events and discovered the SRSF1 binding motif in the regulation of splice switching of PTPMT1. Furthermore, PTPMT1 splice switching was regulated by SRSF1 by binding directly to its motif in E3 which partially mediated the oncogenic role of SRSF1 by the AKT/C-MYC axis. Additionally, PTPMT1 splice switching was validated in tissue samples of BRCA patients and using the TCGA database. The high-risk group, identified by AS of PTPMT1 and expression of SRSF1, possessed poorer prognosis in the stage I/II TCGA BRCA cohort. Conclusions SRSF1 exerts oncogenic roles in BRCA partially by regulating the AS of PTPMT1, which could be a therapeutic target candidate in BRCA and a prognostic factor in HR+ BRCA patient.

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“…LIG1 also plays an important role in DNA replication, as well as the base excision repair process. Although it has not been widely considered as an anti-cancer target molecule, many studies have reported that LIG1 abnormalities are associated with multiple tumorigenesis [35]. In this study, we found that CA signi cantly downregulated LIG1, which may lead to a disruption in DNA synthesis in bladder cancer cells.…”

Section: Discussionmentioning

confidence: 48%

Transcriptome and Proteome Analysis Reveals Corosolic Acid Inhibiting Bladder Cancer via Targeting Cell Cycle and Inducing Mitophagy in Vitro and in Vivo

Cui

et al. 2021

Preprint

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Background Existing chemotherapy and radiotherapy methods have drawbacks such as high toxicity, high side effects, poor efficacy, and chemoresistance. Therefore, there is an urgent need to develop new anti-cancer drugs with low toxicity and high efficiency for cancer therapy and the prevention of recurrence. Corosolic acid (CA) is a medicine and food homologue and has many biological activities of health care. However, the anti-tumor effects and mechanism of CA in bladder cancer remain unexplored. Methods To study the anticancer effect of CA on bladder cancer cells, CCK8, EdU, high-content living cell imaging experiments were performed. And the mice model was used to verify the anticancer effect and toxicity for mice. To investigate the molecular mechanism of CA inhibition on bladder cancer cells, transcriptomics and proteomics were employed. To further verify the pharmacological mechanism, flow cytometry, RT-qPCR, western blotting and immunofluorescence staining experiments were performed, and the CA targeting molecules were analyzed in combination with our experimental and public clinical data. Results We found that CA inhibited bladder cancer cell proliferation in a concentration- and time-dependent manner. Xenograft experiments showed that CA inhibited the growth of subcutaneous tumors, and had no toxicity in mice. Integration of omics analysis revealed that low concentrations of CA inhibited bladder cancer cells proliferation via attenuating DNA synthesis by downregulating TOP2A and LIG1, and via diminishing mitosis by downregulating CCNA2, CCNB1, CDC20, and RRM2. High concentrations of CA induced cell death not through the apoptotic pathway but through triggering mitophagy pathway via upregulating SQSTM1/P62, NBR1, and UBB. Conclusions CA, a natural compound homologous to medicine and food, inhibits the mitosis of bladder cancer cells at low concentrations, and kills bladder cancer cells by inducing mitophagy at high concentrations. This study provides a comprehensive understanding of the pharmacological mechanism of CA inhibition in bladder cancer for the first time, which is helpful for the development of new anti-tumor drugs based on CA.

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The oncogenic RNA-binding protein SRSF1 regulates LIG1 in non-small cell lung cancer

Cited by 33 publications

References 38 publications

CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1

CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1

Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1

Transcriptome and Proteome Analysis Reveals Corosolic Acid Inhibiting Bladder Cancer via Targeting Cell Cycle and Inducing Mitophagy in Vitro and in Vivo

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