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

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

PROVIDER: PRJNA988816 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25056153.fastq.gz	Fastqsanger.gz
	SRR25056154.fastq.gz	Fastqsanger.gz
	SRR25056155.fastq.gz	Fastqsanger.gz
	SRR25056156.fastq.gz	Fastqsanger.gz
	SRR25056157.fastq.gz	Fastqsanger.gz

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

Project description: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.

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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.

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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.

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