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ZRANB2 and SYF2 mediated splicing programs converging on ECT2 are involved in breast cancer cell resistance to doxorubicin

ABSTRACT: We explored the regulation of alternative splicing in a cell model of breast cancer resistance to doxorubicin, and the impact of the depletion of two splicing factors (ZRANB2 and SYF2) in this context.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126365 | GEO | 2019/09/15

REPOSITORIES: GEO

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ZRANB2 and SYF2 mediated splicing programs converging on ECT2 are involved in breast cancer cell resistance to doxorubicin

Project description:ZRANB2 and SYF2 mediated splicing programs converging on ECT2 are involved in breast cancer cell resistance to doxorubicin

| PRJNA521712 | ENA

ZRANB2 and SYF2-mediated splicing programs converging on ECT2 are involved in breast cancer cell resistance to doxorubicin.

Project description:Besides analyses of specific alternative splicing (AS) variants, little is known about AS regulatory pathways and programs involved in anticancer drug resistance. Doxorubicin is widely used in breast cancer chemotherapy. Here, we identified 1723 AS events and 41 splicing factors regulated in a breast cancer cell model of acquired resistance to doxorubicin. An RNAi screen on splicing factors identified the little studied ZRANB2 and SYF2, whose depletion partially reversed doxorubicin resistance. By RNAi and RNA-seq in resistant cells, we found that the AS programs controlled by ZRANB2 and SYF2 were enriched in resistance-associated AS events, and converged on the ECT2 splice variant including exon 5 (ECT2-Ex5+). Both ZRANB2 and SYF2 were found associated with ECT2 pre-messenger RNA, and ECT2-Ex5+ isoform depletion reduced doxorubicin resistance. Following doxorubicin treatment, resistant cells accumulated in S phase, which partially depended on ZRANB2, SYF2 and the ECT2-Ex5+ isoform. Finally, doxorubicin combination with an oligonucleotide inhibiting ECT2-Ex5 inclusion reduced doxorubicin-resistant tumor growth in mouse xenografts, and high ECT2-Ex5 inclusion levels were associated with bad prognosis in breast cancer treated with chemotherapy. Altogether, our data identify AS programs controlled by ZRANB2 and SYF2 and converging on ECT2, that participate to breast cancer cell resistance to doxorubicin.

| S-EPMC7049692 | biostudies-literature

Exon arrays from HeLa cells transfected with GFP-ZRANB2 vector

Project description:Human ZRANB2 mRNA is alternatively spliced to give two variants with different 3M-bM-^@M-^Y ends. Both isoforms are present in the nucleus of human cells. ZRANB2 binds to mRNA, as well as the essential splicing factors U170K and U2AF35, and the novel splicing component SFRS17A (formerly known as XE7). It has been shown to alter splicing patterns of Tra2M-NM-21 minigene primary transcripts in a dose-dependent manner. It is still unclear what role ZRANB2 plays in the regulation of alternative splicing. To determine the endogenous transcripts that are targeted by ZRANB2 at the genome wide level, we decided to perform exon microarray studies and analyzed the suitability of this method to examine splicing differences in human cells overexpressing a splicing factor. GFP-ZRANB2 construct containing isoform 2 (short form, SF) of ZRANB2 was used. This construct includes exon 1 through to alternative exon 10. Isoform 2 was chosen since it has been shown previously to affect alternative splicing of a Tra2M-NM-21 minigene. HeLa cells were transfected with GFP-ZRANB2, control vector GFP or were left untransfected. RNA was extracted using a Qiagen RNA extraction kit. Experiments were run in 5 replicates.

2012-12-15 | E-GEOD-32932 | biostudies-arrayexpress

Exon arrays from HeLa cells transfected with GFP-ZRANB2 vector

Project description:Human ZRANB2 mRNA is alternatively spliced to give two variants with different 3’ ends. Both isoforms are present in the nucleus of human cells. ZRANB2 binds to mRNA, as well as the essential splicing factors U170K and U2AF35, and the novel splicing component SFRS17A (formerly known as XE7). It has been shown to alter splicing patterns of Tra2β1 minigene primary transcripts in a dose-dependent manner. It is still unclear what role ZRANB2 plays in the regulation of alternative splicing. To determine the endogenous transcripts that are targeted by ZRANB2 at the genome wide level, we decided to perform exon microarray studies and analyzed the suitability of this method to examine splicing differences in human cells overexpressing a splicing factor.

2012-12-15 | GSE32932 | GEO

Genes involved in doxorubicin drug resistance in 143b osteosarcoma cell line

Project description:The study was done to identify the differentially expressed genes in response to Doxorubicin drug resistance in the 143B human osteosarcoma cell line, using the Microarray technology. Keywords: drug resistance; dual channel; cell line based; doxorubicin resistance; Human osteosarcoma cell line

2007-03-01 | GSE3362 | GEO

Detoxifying doxorubicin

Project description:Detoxifying doxorubicin

| PRJNA422761 | ENA

Compartment-specific and HuR-coordinated regulation of intronic polyadenylation isoforms by doxorubicin [3-seq]

Project description:We explored the regulation of intronic polyadenylation (IPA) isoforms by doxorubicin and HuR in several subcellular compartments.

2022-06-09 | GSE180847 | GEO

Compartment-specific and HuR-coordinated regulation of intronic polyadenylation isoforms by doxorubicin [total RNA-seq]

Project description:We explored the regulation of intronic polyadenylation (IPA) isoforms by doxorubicin and HuR in breast cancer cells.

2022-06-09 | GSE180849 | GEO

Detoxifying doxorubicin

Project description:The anthracycline doxorubicin is a highly effective anti-cancer drug associated with severe side effects, including secondary tumors and cardiotoxicity. Doxorubicin induces DNA damage through double-strand breaks (DSBs) and epigenetic or chromatin damage through histone eviction. We examined whether separation of these activities can help to detoxify doxorubicin, while maintaining its chemotherapeutic efficacy. We show that anthracycline variants harboring the histone eviction activity alone remain potent anti-cancer drugs, while greatly alleviating cardiotoxicity and secondary tumor formation. We thus demonstrate that treatment-limited side effects of doxorubicin can be synthesized away, yielding effective chemotherapeutics towards improved and prolonged treatment responses and higher patient quality of life.

2019-09-01 | GSE108179 | GEO

Role of Aldoketoreductases and Other Doxorubicin Pharmacokinetic Genes in Doxorubicin Resistance, DNA binding, and Subcellular Localization

Project description:Objective: To assess the role of aldoketoreductases and other doxorubicin pharmacokinetic or pharmacogenomic genes in doxorubicin cytotoxicity, resistance, DNA binding activity, and subcellular localization, Methods: We conducted a whole genome microarray study to identify differences in between doxorubicin-sensitive MCF-7cc cells and doxorubicin-resistant MCF-7Dox2-12 cells in terms of their expression of genes related to doxorubicin pharmacokinetics or pharmacodynamics. Targets were then validated by pharmacologic inhibition in conjunction with drug metabolite profiling, drug localization, drug cytotoxicity, and drug DNA binding studies. Results: 2063 differentially expressed transcripts were identified, including 17% and 43% of genes or gene families associated with doxorubicin pharmacokinetics or pharmacodynamics (p values of significance of 0.05 and <0.0001, respectively). The largest changes in the expression of genes associated with doxorubicin pharmacokinetics and pharmacodynamics were chiefly among the aldo-keto reductases (AKRs) Akr1c2, Akr1c3 and Akr1b10 which convert doxorubicin to doxorubicinol. We observed that doxorubicinol exhibits dramatically reduced drug toxicity, reduced drug DNA-binding activity, and altered drug subcellular localization to lysosomes. Pharmacologic inhibition of these AKRs in MCF-7Dox2-12 cells restored drug cytotoxicity, and drug localization to the nucleus. Conclusion: These findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledgebases to identify highly relevant genes associated with doxorubicin resistance. The products of one or more of these genes could effectively be shown to alter the drug’s properties, while inhibiting them restored drug DNA binding, cytotoxicity, and subcellular localization.

2012-11-22 | GSE27254 | GEO

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