Cyclin‐dependent kinase 12 deficiency reprogrammes cellular metabolism to alleviate ferroptosis potential and promote the progression of castration‐resistant prostate cancer

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(5)

Published: May 1, 2024

Abstract Background Cyclin‐dependent kinase 12 (CDK12)‐deficient prostate cancer defines a subtype of castration‐resistant (CRPC) with poor prognosis. Current therapy, including PARP inhibitors, shows minimal treatment efficacy for this CRPC, and the underlying mechanism remains elusive. Methods Based on bioinformatics analysis, we evaluated relationship between CDK12 deficiency patient's prognosis resistance. Furthermore, used CRISPR‐Cas9 technology mass spectrometry‐based metabolomic profiling to reveal metabolic characteristics CDK12‐deficient CRPC. To elucidate specific mechanisms deficiency‐mediated CRPC reprogramming, utilized cell RNA‐seq other molecular biology techniques, cellular reactive oxygen species probes, mitochondrial function assays, ChIP‐qPCR RNA stability analyses, clarify role in regulating its contribution ferroptosis. Finally, through vitro drug sensitivity testing vivo experiments mice, identified therapeutic effects electron transport chain (ETC) inhibitor IACS‐010759 Results cancers reprogramme energy metabolism support their aggressive progression. In particular, enhanced respiratory electronic transfer ATP synthesis create ferroptosis potential cells. However, downregulated ACSL4 expression, which counteracts lipid oxidation stress, leading escape cells from targeting ETC substantially inhibited proliferation vivo, suggesting new target therapy cancer. Conclusions Our findings show that work together drive progression provide insight into worse patients. Key points promotes by reprogramming metabolism. leads more active (ETC), ensuring efficient supply. phosphorylates Pol II ensure transcription regulate Mitochondrial inhibitors exhibit better selectivity cells, offering promising approach

Language: Английский

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Critical role of non-coding RNA-mediated ferroptosis in urologic malignancies

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 31, 2024

Urologic malignancies, characterized by their high aggressiveness and metastatic potential, pose a significant public health challenge globally. Ferroptosis, novel mode of cell death, typically arises from intracellular iron ion overload the accumulation lipid peroxides. This process has been shown to play crucial regulatory role in various pathological conditions, particularly cancer, including urologic cancers. However, comprehensive mechanisms underlying ferroptosis remain poorly understood, which somewhat limits its broader application cancer therapy. Non-coding RNAs (ncRNAs), encompass microRNAs (miRNAs), long non-coding (lncRNAs), circular (circRNAs), are transcripts that pivotal roles physiological processes, such as proliferation, differentiation, apoptosis, cycle regulation, modulating expression target genes. The biological functions potential ncRNAs context cancer-related have partially elucidated. Research indicates can influence progression cancers affecting migration, drug resistance through regulation ferroptosis. Consequently, this review aims clarify ncRNA-ferroptosis axis evaluate clinical significance ferroptosis-related ncRNAs, thereby providing new insights into biology therapeutic strategies may ultimately benefit diverse range patients.

Language: Английский

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Physiological and pathological roles of the transcriptional kinases CDK12 and CDK13 in the central nervous system

Cell Death and Differentiation, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 12, 2024

The cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) govern several steps of gene expression, including transcription, RNA processing translation. main target CDK12/13 is the serine 2 residue carboxy-terminal domain polymerase II (RNAPII), thus influencing directionality, elongation rate processivity enzyme. CDK12/13-dependent regulation RNAPII activity influences expression selected genes with important functional roles in proliferation viability all eukaryotic cells. Neuronal cells are particularly affected by loss CDK12/13, as result high dependency neuronal on for their expression. Deregulation strongly affects brain physiology stemness potential differentiation properties precursor Moreover, mounting evidence also suggest involvement tumours. Herein, we discuss role(s) CDK12 CDK13 highlight similarities differences between these highly homologous kinases, particular attention to impact pathology. Lastly, provide an overview inhibitors efficacy tumours other neoplastic diseases.

Language: Английский

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Roles of CDK12 mutations in PCa development and treatment

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: unknown, P. 189247 - 189247

Published: Dec. 1, 2024

Language: Английский

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Tracking down metabolic vulnerabilities in CDK12‐mutant prostate cancer

Clinical and Translational Discovery, Journal Year: 2024, Volume and Issue: 4(4)

Published: July 19, 2024

CDK12 is among the most frequently mutated cyclin-dependent kinases (CDKs) in various cancers, including prostate, ovarian, breast, esophageal, bladder, and colon cancers.1 Specifically, biallelic aberrations of occur 3%–7% metastatic castration-resistant prostate cancer (mCRPC) cases correlate with poor prognosis.1 One well-studied functions its orchestration transcription initiation elongation through cyclin K-dependent Ser2 phosphorylation RNA polymerase II,2 therefore important regulating expression long genes or high exon numbers, especially DNA damage response (DDR)-related such as BRCA1, ATR, FANCI, FANCD21.3 As a result, CDK12-deficient cancers are commonly characterized by focal tandem duplications (FTDs) features genome instability.4, 5 Because FTDs often generate large amount neoantigens, it has been suggested that tumours may be more sensitive to immunotherapy.5 However, studies immune checkpoint blockade therapy have shown only limited effects mCRPC patients harbouring mutations.6 Likewise, despite observed sensitization ovarian cells PARP inhibitors (PARPi) due impaired DDR functionality,7 clinical trials PARPi produced unsatisfactory results Therefore, there an urgent need identify exploitable vulnerabilities cancer. In recent study, Zhang et al. investigated impact deficiency on cell metabolism tumour progression cancer.8 By analyzing public datasets, they confirmed association between prognosis mCRPC, while noting higher levels mutations Chinese (15.4%–27.2%) than global populations (4.7%). To further delineate how promotes generated CDK12-knockout lines using CRISPR-Cas9 technology conducted metabolomic transcriptomic analyses. The resulting data showed reprogrammed energy metabolisms cells; specifically, knockout exhibited metabolites related glycolysis, glutaminolysis, tricarboxylic acid cycle, but lower β-oxidation. Further, associated RNA-seq enrichment mitochondrial electron transport chain (ETC) oxidative phosphorylation-related pathways suggesting enhancing ETC-dependent production (Figure 1). team also found consistently significantly increased adenosine triphosphate (ATP) compared controls. ETC activity previously generation reactive oxygen species, which induce types death ferroptosis. Ferroptosis, form regulated driven iron-dependent lipid peroxidation, was recently identified emerging therapeutic target range cancer.9 tested whether ferroptosis could potential vulnerability context deficiency. Surprisingly, depletion intracellular antioxidant substances cysteine glutathione upregulation, were resistant inducers, RSL3 erastin, control cells. Mechanistically, dysregulation metabolism-related alterations involved phospholipid biosynthesis pathway typical reduced their susceptibility probed further, ACSL4 all downregulated gene correlated sensitivity. ChIP assays demonstrated direct binding II 6 sequence upon loss both C4-2 PC-3 mRNA stabilization fractionally contributed loss-induced downregulation. Though unclear regulates stability, modifications N6-methyladenosine (m6A) involved, reported lactate, here elevated cells, METTL3-mediated m6A modification stability.10 While primary recognized function centers elongation, interacting factor mechanisms governing specific rather remain unclear. Understanding subsets hold significant promise for development novel therapies minimal side effects. Intriguingly, showing ferroptosis-resistant phenotype, vulnerable inhibitors, specifically complex I applying inhibitor, IACS-010759, able show effective suppression vitro vivo. Previous enzalutamide-resistant dependence enzalutamide-sensitive targeting metabolism.11 Moreover, mutation develop rapidly.12 Collectively, these suggest upregulating activity, potentially serve promising strategy managing particularly those CDK12-mutant Wei-Ling Tu, Mu-En Wang, Ming Chen preparation, writing, editing manuscript. We would like thank current members Laboratory critical discussion this topic Thomas Garvey authors declared no conflict interest. This work supported NIH grants (R01 CA269211 R01 CA266510) Idea Development Award from Department Defense Prostate Cancer Research Program (W81XWH2010185) Chen. Wang part Early Investigator (W81XWH2211005). Not applicable.

Language: Английский

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New insights into the dule roles CDK12 in human cancers: mechanisms and interventions for cancer therapy

Journal of Pharmaceutical Analysis, Journal Year: 2024, Volume and Issue: unknown, P. 101173 - 101173

Published: Dec. 1, 2024

Language: Английский

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