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PTBP1 Regulates DNMT3B Alternative Splicing by Interacting with RALY to Enhance the Radioresistance of Prostate Cancer

ABSTRACT: Radiotherapy is a curative arsenal for prostate cancer (PCa), but radioresistance seriously compromises its effectiveness. Dysregulated RNA splicing factors are extensively involved in tumor progression. Nonetheless, the role of splicing factors in radioresistance remains largely unexplored in PCa. Here, we identified 23 splicing factors that are differentially expressed between PCa and adjacent normal tissues across multiple public PCa databases. Among those genes, polypyrimidine tract binding protein 1 (PTBP1) was significantly upregulated in PCa and was positively associated with advanced clinicopathological features and poor prognosis. Gain- and loss-of-function experiments demonstrated that PTBP1 markedly reinforced genomic DNA stability to desensitize PCa cells to irradiation in vitro and in vivo. Mechanistically, PTBP1 interacted with the HnRNP associated with lethal yellow protein homolog (RALY) and regulated exon 5 splicing of methyltransferase 3b (DNMT3B) from DNMT3B-S to DNMT3B-L. Furthermore, upregulation of DNMT3B-L induced promoter methylation of dual-specificity phosphatase-2 (DUSP2) and subsequently inhibited DUSP2 expression, thereby increasing radioresistance in PCa. Our findings highlight the role of splicing factors in inducing aberrant splicing events in response to radiotherapy and the potential role of PTBP1 and DNMT3B-L in reversing radioresistance in PCa.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276977 | GEO | 2025/01/01

REPOSITORIES: GEO

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PTBP1 Regulates DNMT3B Alternative Splicing by Interacting with RALY to Enhance the Radioresistance of Prostate Cancer

Project description:PTBP1 Regulates DNMT3B Alternative Splicing by Interacting with RALY to Enhance the Radioresistance of Prostate Cancer

| PRJNA1159875 | ENA

Regulation of co-transcriptional splicing by RNA-binding protein PTBP1

Project description:We examined the role of PTBP1 in regulation of co-transcriptional splicing process by depleting this RNA-binding protein from embryonic stem cells using the auxin-inducible degron technology and analysing the total and chromatin-associated RNA fractions by RNA-seq. We also performed mNET-seq and ChIP-seq analyses using RNA polymerase II- and PTBP1-specific antibodies, respectively. Our data suggest that PTBP1 activates co-transcriptional splicing of hundreds of introns, a surprising effect given that PTBP1 is better known as a splicing repressor. Importantly, some co-transcriptionally activated introns fail to be spliced post-transcriptionally without PTBP1. In a striking example of this regulation, lasting retention of a PTBP1-dependent intron triggers nonsense-mediated decay of mRNAs encoding DNA methyltransferase DNMT3B, explaining their natural expression dynamics in development. Our further analyses suggest that this mechanism may protect differentiation-specific genes from aberrant methylation. We conclude that PTBP1-activated co-transcriptional splicing underlies biologically important decisions.

2023-01-08 | E-MTAB-11544 | biostudies-arrayexpress

Transcriptomic analysis of senescent cells upon EXOC7 knockdown.

Project description:IMR90 ER:RAS cells were transfected with scramble siRNA or 2 deconvoluted siRNAs targeting EXOC7 or an siRNA targeting PTBP1. The next day the cells were treated with 4OHT to induce senescence. 5 days later the cells were collected for total mRNA analysis. Our previous experiments had shown that alternative splicing of EXOC7 depends on PTBP1 and PTBP1 is a target for suppressing pro-inflammatory factors in senescence. By performing RNA-seq we confirmed that the pro-inflammatory factors whose expression depends on PTBP1 equally depends on EXOC7.

2018-06-25 | GSE101758 | GEO

Gene expression in radio-sensitive or -resistant breast cancer cells [MCF-7]

Project description:During radiotherapy most cancer cells are removed, but some cells are not. These remained cancer cells become resistant to radiotherapy and lead to cancer recurrence. Radioresistnat cancer cells show different gene expression profile than radiosensitive tumor cells. Among the genes distinctly up or down-changed in expression level, some are associated with development of radioresistance. We used microarrays to select multiple genes showing distinct change in expression level for seeking genes that contribute to the develpoment of radioresistance in breast cancer cells during radiotherapy.

2022-05-31 | GSE175490 | GEO

Gene expression in radio-sensitive or -resistant breast cancer cells

2021-09-18 | GSE158132 | GEO

Androgen receptor splicing variant 7 (ARv7) promotes DNA damage response in prostate cancer cells

Project description:In the treatment of patients with locally advanced prostate cancer (PCa), androgen deprivation therapy (ADT) significantly enhances the efficacy of radiotherapy by weakening the DNA damage response (DDR) pathway. Recently, several studies have suggested that androgen receptor splicing variants (ARvs) may mediate a compensatory DDR pathway when canonical androgen receptor (AR) signaling is inhibited, thus contributing to the resistance of some patients to this combinational treatment. However, the specific roles of certain ARvs as well as the detailed mechanism of how ARvs regulate the DDR are not well understood. Here, we demonstrated that AR splicing variant 7 (ARv7), which is the most abundant form of ARvs, significantly promotes the DDR of PCa cells under severe DNA damage independent of its parental AR by using the ionizing radiation (IR) and doxorubicin (Dox)-treated cell models. Mechanistically, ARv7 is sufficient to upregulate both the homologous recombination (HR) and the nonhomologous end joining (NHEJ) pathways by forming a positive regulatory loop with poly ADP-ribose polymerase 1 (PARP1). Moreover, the presence of ARv7 impairs the synergistic effect between AR antagonists and poly ADP-ribose polymerase (PARP) inhibitor, which has been recently shown to be a promising future treatment strategy for metastatic castration resistant prostate cancer (mCRPC). Combined, our data indicate that constitutively active ARv7 not only contributes to radioresistance after ADT, but may also serve as a potential predictive biomarker for assessing the efficacy of novel PARP inhibitor-based therapy in PCa.

2024-09-14 | GSE277204 | GEO

Tissue samples of 4 patients with esophageal cancer before and after radiotherapy

Project description:Esophageal cancer is one of the common malignant tumors, and the mortality rate ranks fourth among all malignant tumors in China. Radiotherapy is one of the main methods for the treatment of esophageal cancer, and radiation resistance is one of the important factors of tumor recurrence and metastasis. Therefore, the study of radioresistance related markers of esophageal cancer is of great significance to improve the radiosensitivity of esophageal cancer. We used microarrays to detail to find critical prognostic factors for esophageal cancer patients after radiotherapy.

2021-06-16 | GSE137867 | GEO

Gene Expression and Exon Splicing Change Analysis of Mouse N2A Cell Transcriptome upon Polypyrimidine tract-binding protein depletion.

Project description:Purpose : Splicing factors regulate splice site choices in pre-mRNA and determine final exon set in mRNA. To understand mechanisms of splicing regulation, it is important to identify and characterize exon targets of splicing factors. Recently, development of RNA-seq technology enables researchers to investigate exon splicing profiles as well as gene expression profiles in transcriptome-wide. The goal of this study is to investigate transcriptome changes by splicing factors, Polypyrimidine Tract Binding proteins (PTB). In this study, we analyzed exon and gene expression changes followed by Ptbp1 knock down. Methods : The knockdown experiment was performed in mouse neuroblastoma (N2A) cells. Total RNA was collected from cells and further treated with DNase I to avoid DNA contamination. RNA-seq libraries were constructed in a strand specific way using dUTP and Uracil-Specific Excision Reagent enzyme. The libraries were subjected to 100bp paired-end sequencing (Illumina HiSeq2000 platform). Poly(A)-mRNA and exon profiles of N2A mouse blastoma cells in two samples: shRNA transfection control, single knock down of ptbp1. RNA-seq libraries were generated in strand specific way using dUTP and USER enzyme and sequenced using Illumina HiSeq2000.

2013-12-01 | E-GEOD-45119 | biostudies-arrayexpress

Splicing analyses of 46C mNPCs following PTBP depletion

Project description:PTBP1 and PTBP2 control alternative splicing programs during neuronal development, but the cellular functions of most PTBP1/2-regulated isoforms remain unknown. We show that PTBP1 guides developmental gene expression by regulating the transcription factor Pbx1. We identify exons that are differentially spliced when mouse embryonic stem cells (ESCs) differentiate into neuronal progenitor cells (NPCs) and neurons, and transition from PTBP1 to PTBP2 expression. We define those exons controlled by PTBP1 in ESCs and NPCs by RNA-seq analysis after PTBP1 depletion and PTBP1 crosslinking-immunoprecipitation. We find that PTBP1 represses Pbx1 exon 7 and the expression of its neuronal isoform Pbx1a in ESC. Using CRISPR-Cas9 to delete regulatory elements for exon 7, we induce Pbx1a expression in ESCs, finding that this activates transcription of specific neuronal genes including known Pbx1 targets. Thus PTBP1 controls the activity of Pbx1 and suppresses its neuronal transcriptional program prior to differentiation. 46C mESCs were differentiated in mNPCs. The mNPCs were treated with 10 nM control, Ptbp1, Ptbp2, or Ptbp1 and Ptbp2 siRNAs for 48 hours. The knockdowns were performed using 2 independent sets of siRNAs. Poly-A RNA was isolated for RNA-sequencing and splicing analyses.

2016-07-03 | E-GEOD-70985 | biostudies-arrayexpress

Splicing analyses of 46C mESCs following PTBP depletion

Project description:PTBP1 and PTBP2 control alternative splicing programs during neuronal development, but the cellular functions of most PTBP1/2-regulated isoforms remain unknown. We show that PTBP1 guides developmental gene expression by regulating the transcription factor Pbx1. We identify exons that are differentially spliced when mouse embryonic stem cells (ESCs) differentiate into neuronal progenitor cells (NPCs) and neurons, and transition from PTBP1 to PTBP2 expression. We define those exons controlled by PTBP1 in ESCs and NPCs by RNA-seq analysis after PTBP1 depletion and PTBP1 crosslinking-immunoprecipitation. We find that PTBP1 represses Pbx1 exon 7 and the expression of its neuronal isoform Pbx1a in ESC. Using CRISPR-Cas9 to delete regulatory elements for exon 7, we induce Pbx1a expression in ESCs, finding that this activates transcription of specific neuronal genes including known Pbx1 targets. Thus PTBP1 controls the activity of Pbx1 and suppresses its neuronal transcriptional program prior to differentiation. 46C mESCs were treated with 20 nM control, Ptbp1, Ptbp2, or Ptbp1 and Ptbp2 siRNAs for 72 hours. The knockdowns were performed using 2 independent sets of siRNAs, including one biological replicate. Poly-A RNA was isolated for RNA-sequencing and splicing analyses.

2016-07-03 | E-GEOD-71075 | biostudies-arrayexpress

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