Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Effect of inhibition of SRPK1 and CDK12 on transcription and splicing in castration resistance prostate cancer cells

ABSTRACT: Inactivation of CDK12 characterizes an aggressive sub-group of castration-resistant prostate cancer (CPRC), and CRPC is currently a lethal disease. Hyper-activation of MYC transcription factor is sufficient to confer the CRPC-phenotype. Here, we show that the loss of CDK12 promotes MYC activity, which renders the cells addicted on the splicing regulatory kinase SRPK1. High MYC expression is associated with increased levels of SRPK1 in patient samples, and over-expression of MYC sensitizes prostate cancer cells to SRPK1 inhibition using pharmacological and genetic strategies. We show that Endovion (SCO-101), a compound currently in clinical trials against pancreatic cancer, phenocopies the effects of the well-characterized SRPK1 inhibitor (SRPIN340) on the nascent transcription, splicing and the overall transcriptional program. Inhibition of SRPK1 with either of the compounds promotes transcription elongation, causes defects in splicing and transcriptionally activates the unfolded protein response. In brief, here we show that CDK12 inactivation promotes MYC-signaling in an SRPK1-dependent manner and identify the clinical grade compound Endovion, which selectively targets the cells with CDK12 inactivation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236089 | GEO | 2024/10/16

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 As A Candidate Therapeutic Target

Project description:Protein kinases (collectively termed the kinome) represent one of the most tractable drug targets in the pursuit of new and effective cancer treatments. However, less than 20% of the kinome is currently being explored as primary targets for cancer therapy, leaving the majority of the kinome untargeted for drug therapy. Chemical proteomics approaches such as Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS) have been developed that measure the abundance of a significant proportion of the kinome, providing a strategy to interrogate kinome landscapes and dynamics. Kinome profiling of cancer cell lines using MIB-MS has been extensively characterized, however, the application of this method to measure tissue kinome(s) has not been thoroughly explored. Here, we present a quantitative proteomics workflow specifically designed for kinome profiling of tissues that pairs MIB-MS with a newly designed s-SILAC kinome standard. Using this workflow, we mapped the kinome landscape of endometrial carcinoma (EC) tumors and normal endometrial (NE) tissues and identified several kinases overexpressed in EC tumors, including Serine/Arginine-Rich Splicing Factor kinase, (SRPK1). Immunohistochemical (IHC) analysis of EC tumor TMAs confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Inhibition of SRPK1 in USC cells altered mRNA splicing, downregulating several oncogenes including MYC and Survivin resulting in apoptosis. Taken together, we present a SILAC-based MIB-MS kinome profiling platform for measuring kinase abundance in tumor tissues, and demonstrate its application to identify SRPK1 as a plausible kinase drug target for the treatment of EC.

2020-09-30 | PXD020357 | Pride

Differences in gene expression in CRPC cell line C4-2 before and after Cyclin-Dependent Kinase 12 (CDK12) knockdown using CRISPR-Cas9

Project description:CDK12 is a transcription-related CDK that is commonly mutated in different types of cancers. In prostate cancer, defective CDK12 has been identified as a new subtype with a worse prognosis and widespread drug resistance. CRPC is a malignant stage of recurrent prostate cancer following treatment, with a higher frequency of CDK12 mutations compared to early-stage prostate cancer. To investigate the impact of CDK12 defects on the overall gene expression in CRPC cells, we used CRISPR-Cas9 technology to generate CDK12 knockout and control C4-2 cell lines, followed by high-throughput transcriptome sequencing (RNA-seq). Our results demonstrate that CDK12 defects affect the expression of numerous genes in CRPC cells, providing insights into the regulatory role of CDK12 in prostate cancer development.

2024-01-17 | GSE246983 | GEO

SPRK1 shRNA and overexpression followed by RNA-seq in glioblastoma cells

Project description:SRPK1 is an SR (serine-arginine) protein kinase with an emerging role as a therapeutic target. SRPK1 phosphorylates the SR family of core spliceosomal components and accessory splicing factors, representing a pivotal regulator of splicing events in human cells. Because alternative splicing of mRNAs in the nervous system occurs at high frequency, the imbalance of mRNA isoforms can affect the function of important neural proteins. We used this RNA-seq dataset to classify splicing events upon genetic modulation of SRPK1, in glioblastoma cells.

2023-05-15 | GSE203177 | GEO

CDK12 Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality [RNA-Seq]

Project description:Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development—either alone, or in the context of other genetic alterations—and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with p53 inactivation, but negatively associated with Pten inactivation—similar to what is seen in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent p53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic CDK12 and p53 loss allografts represent a new syngeneic model for the study of prostate cancer. Cdk12-null organoids (either with or without p53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and paralog-based synthetic lethality is a promising strategy for treating CDK12 mutant mCRPC.

2024-04-17 | GSE254388 | GEO

CDK12 Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality [scRNA-Seq]

2024-04-17 | GSE254387 | GEO

Characterizing the molecular features of ERG-positive tumors in primary and castration resistant prostate cancer

Project description:This study examined ERG expression in primary PCa and CRPC. We have identified altered levels of inflammatory mediators associated with ERG expression and a novel ERG-associated protein, DCLK1, which may play a role in primary PCa progression to metastatic CPRC.

2016-02-01 | GSE74367 | GEO

CDK12 and Integrator-PP2A complex Modulates LEO1 Phosphorylation for Processive Transcription Elongation

Project description:Cyclin-dependent kinase 12 (CDK12) interacts with Cyclin K to form a functional nuclear kinase that promotes processive transcription elongation through phosphorylation of the RNA polymerase II (Pol II) C-terminal domain (CTD). To gain a broader understanding of CDK12 cellular function, we used chemical-genetic and phosphoproteomic screening to identify a landscape of nuclear human CDK12 substrates, including regulators of transcription, chromatin organization, and RNA splicing. We further validated LEO1, a subunit of the PAF1 complex (PAF1C), as a bona fide cellular substrate of CDK12. Acute depletion of LEO1, or substituting LEO1 phosphorylation sites with alanine, attenuated PAF1C association with elongating Pol II and impaired processive transcription elongation. We also found that LEO1 interacts with, and is dephosphorylated by, the Integrator-PP2A complex (INTAC) and that INTAC promotes the association of PAF1C with Pol II. Together, this study reveals a previously unknown role for CDK12 and INTAC in regulating LEO1 phosphorylation for transcriptional regulation, providing important insights into gene transcription and its regulation.

2023-06-08 | PXD038558 | Pride

CDK12 regulates co-transcriptional splicing and RNA turnover in human cells

Project description:The cyclin-dependent kinase CDK12 promotes transcription completion of long genes by suppressing the utilization of intronic polyadenylation sites that cause premature transcriptional termination. One class of genes that are particularly affected by loss of CDK12 activity are DNA damage response genes and therefore inhibitors of CDK12 have garnered interest as cancer therapeutic amplifiers. In this study, we used the CDK12/13 inhibitor THZ531 to treat HF1 (normal human fibroblasts), K562 and HeLa cells and the adenine analog 1-NM-PP1 to treat analog-sensitive HeLa cells and to assess the acute effects on transcription and RNA processing using Bru-seq and BruChase-seq. While acute transcriptional changes were small and limited to the 3’-ends of genes, RNA turnover was dramatically affected by CDK12 inhibition. Importantly, the downregulation of DNA damage response genes was predominantly due to increased mRNA turnover. Co-transcriptional splicing was suppressed by CDK12 inhibition. Finally, many introns that showed premature transcriptional termination were found to be resistant to degradation following CDK12 inhibition despite showing efficient splicing. We speculate that premature termination and addition of poly(A)s protect these spliced intronic fragments from degradation. These studies reveal previously unknown roles of CDK12 in regulating RNA turnover and co-transcriptional splicing.

2022-09-17 | GSE191222 | GEO

Evaluating genome-wide expression following the disruption of CDK12 reveals a bimodal pattern of gene regulation

Project description:We demonstrate that the loss of CDK12 protein or activity, unlike CDK9 or CDK7, significantly upregulates the expression of certain genes, including genes whose activation contributes to the anti-proliferative effects of CDK12 inhibition. In HER2+ breast cancer, a malignancy where CDK12 is almost invariably co-amplified with HER2, CDK12 inhibition drives up the expression of MYC, which is toxic to HER2+ cancer cells. This upregulation of c-myc largely mediates the killing effect of CDK12 inhibition. Therefore, we report a novel mode of regulation of gene expression via CDK12, which represents a promising target for cancer driven by HER2 gene amplification.

2024-02-12 | GSE181905 | GEO

MYC and p53 cooperate through VEGF signaling to repress cytotoxic T cell and immunotherapy responses in prostate cancer

Project description:To study the genetic factors that influence the immune landscape of castration-resistant prostate cancer (CRPC), we utilized a flexible, electroporation-based system to introduce genetic alterations relevant to human disease directly into the prostate glands of mice. These electroporation-based genetically engineered mouse models (EPO-GEMM) recapitulate features of traditional models, and allow us to investigate distinct genetic subtypes of prostate cancer within an intact tumor-immune microenvironment. We observed differences between genetic subtypes of CRPC, with MYC-driven subtypes exhibiting a "cold" immune landscape compared to others. Interestingly, we found that the compound loss of different tumor suppressors such as Pten or p53 with MYC further impacts the inflammatory profile of prostate cancer, with MYC and p53 (MP) alterations cooperating to drive VEGF expression and immune suppression. VEGF signaling blockade resulted in re-activation of cytotoxic T cell anti-tumor immunity and restored sensitivity to immunotherapy in MP CRPC. Thus, by leveraging the power of EPO-GEMMs to generate distinct subtypes of CRPC, our studies reveal a functional role for VEGF signaling in driving prostate cancer immune evasion and validate the VEGF pathway as an actionable therapeutic target in MYC and p53 altered prostate cancer.

2024-08-26 | GSE271975 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data