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

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

PROVIDER: PRJNA521712 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8556620_1.fastq.gz	Fastqsanger.gz
	SRR8556620_2.fastq.gz	Fastqsanger.gz
	SRR8556630_1.fastq.gz	Fastqsanger.gz
	SRR8556630_2.fastq.gz	Fastqsanger.gz
	SRR8556621_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

2019-09-15 | GSE126365 | GEO

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

RNA-seq of WT (Col-0) and ect2 in Arabidopsis

Project description:RNA-seq of WT (Col-0) and ect2 to study the differentially expressed genes.

2018-06-21 | GSE108118 | GEO

FoxM1 insufficiency hyperactivates Ect2-RhoA-mDia1 signaling to drive cancer

Project description:FoxM1 activates genes that regulate S-G2-M cell-cycle progression and, when overexpressed, is associated with poor clinical outcome in multiple cancers. Here we identify FoxM1 as a tumor suppressor in mice that, through its N-terminal domain, binds to and inhibits Ect2 to limit the activity of RhoA GTPase and its effector mDia1, a catalyst of cortical actin nucleation. FoxM1 insufficiency impedes centrosome movement through excessive cortical actin polymerization, thereby causing the formation of non-perpendicular mitotic spindles that missegregate chromosomes and drive tumorigenesis in mice. Importantly, low FOXM1 expression correlates with RhoA GTPase hyperactivity in multiple human cancer types, indicating that suppression of the newly discovered Ect2-RhoA-mDia1 oncogenic axis by FoxM1 is clinically relevant. Furthermore, by dissecting the domain requirements through which FoxM1 inhibits Ect2 GEF activity, we provide mechanistic insight for the development of pharmacological approaches that target protumorigenic RhoA activity.

2020-07-09 | GSE130410 | GEO

ECT2 promotes proliferation and metastasis of esophageal squamous cell carcinoma（ESCC） via Rho-ERK-VEGF/MMP9 signaling pathway

Project description:In order to analyze the difference in the whole gene expression profile of ESCC(esophageal squamous cell carcinoma) and normal adjecent esophageal tissue as well as cancer metastasis tissue. We found that ECT2 (Epithelial cell transformation sequence 2) is highly expressed in esophageal squamous cell carcinoma compared with adjacent normal tissues by microarray analysis, and we further analyzed the expression of ECT2 in 40 patients by qRT-PCR, and found that ECT2 is indeed high in cancer tissues. Expressed in normal tissues adjacent to cancer. We first confirmed the overexpression of ECT2 in ESCC, further confirming the signaling pathway in the oncogenisis of ESCC.

2022-07-08 | GSE138570 | GEO

Phoshorylation regulated UBF1 and ECT2 Binding on ribosomal DNA

Project description:Epithelial Cell Transforming Sequence 2 (ECT2), a guanine nucleotide exchange factor (GEF) for Rho GTPases, is overexpressed in many cancers and is involved in signal transduction pathways that promote cancer cell proliferation, invasion and tumorigenesis. Recently, we demonstrated that a significant pool of ECT2 localizes to the nucleolus of non small cell lung cancer (NSCLC) cells where it binds the transcription factor Upstream Binding Factor 1 (UBF1) on the promoter regions of the ribosomal DNA (rDNA) and activates rDNA transcription, transformed growth and tumor formation. Here we investigate the mechanism by which ECT2 engages UBF1 on rDNA. Mutagenesis of ECT2 demonstrates that the tandem BRCT domain of ECT2 mediates binding to UBF1. Biochemical and mass spectrometry analysis reveals that Protein Kinase Ci (PKCi) directly phosphorylates UBF1 at Ser412 to generate a phosphopeptide binding epitope that binds the ECT2 BRCT domain. Lentiviral shRNA knockdown and reconstitution experiments demonstrate that both a functional ECT2 BRCT domain and the UBF1 Ser412 phosphorylation site are required for UBF1 mediated ECT2 recruitment to rDNA, elevated rRNA synthesis and transformed growth. Taken together, our study provides new molecular insight into ECT2 mediated regulation of rDNA transcription in cancer cells and provides a rationale for therapeutic targeting of UBF1 and ECT2 stimulated rDNA transcription for the treatment of NSCLC.

2020-04-10 | MSV000085269 | MassIVE

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

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Detoxifying doxorubicin

Project description:Detoxifying doxorubicin

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ECT2 associated to PRICKLE1 are poor-prognosis markers in triple-negative breast cancer

Project description:Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and the lack of specific signature makes difficult the development of targeted therapeutic strategy. We previously found that PRICKLE1, an evolutionary conserved protein acting as a regulator of vertebrate development, is upregulated in TNBC. Proteomic approaches allowed us to decipher the protein complex associated to PRICKLE1 in TNBC. Within that complex, we identified a large subset of proteins involved in the regulation of Rho-GTPase family members. We build a metagene with regulators of small G-protein activity and we found that this metagene is overexpressed in TNBC and is a poor prognosis marker. We analyzed the combination of the metagene expression and PRICKLE1 expression and identified that combined expression of ECT2 and PRICKLE1 provides a worst prognosis than PRICKLE1 expression alone in TNBC. ECT2 is a GEF for Rac1 and we showed that PRICKLE1 regulate the enzymatic activity of ECT2. Finally, we also observed that Ect2 and Prickle1 are functionally connected during evolution since both act synergistically to coordinate cellular movement during vertebrate gastrulation. Our results demonstrate the pivotal role of PRICKLE1 in TNBC and build the path for development of targeted therapeutic strategies to heal TNBC patients.

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Expression data of HUVEC exposed to an atheroprotective shear stress waverform in the presence of Doxorubicin

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2021-02-01 | GSE111129 | GEO

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