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Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects.

ABSTRACT: Direct tubular injury caused by several medications, especially chemotherapeutic drugs, is a common cause of AKI. Inhibition or loss of cyclin-dependent kinase 12 (CDK12) triggers a transcriptional elongation defect that results in deficiencies in DNA damage repair, producing genomic instability in a variety of cancers. Notably, 10-25% of individuals developed AKI after treatment with a CDK12 inhibitor, and the potential mechanism is not well understood. Here, we found that CDK12 was downregulated in the renal tubular epithelial cells in both patients with AKI and murine AKI models. Moreover, tubular cell-specific knockdown of CDK12 in mice enhanced cisplatin-induced AKI through promotion of genome instability, apoptosis, and proliferative inhibition, whereas CDK12 overexpression protected against AKI. Using the single molecule real-time (SMRT) platform on the kidneys of CDK12^RTEC+/- mice, we found that CDK12 knockdown targeted Fgf1 and Cast through transcriptional elongation defects, thereby enhancing genome instability and apoptosis. Overall, these data demonstrated that CDK12 knockdown could potentiate the development of AKI by altering the transcriptional elongation defect of the Fgf1 and Cast genes, and more attention should be given to patients treated with CDK12 inhibitors to prevent AKI.

SUBMITTER: Zhang YL

PROVIDER: S-EPMC10929189 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects.

Zhang Yi-Lin YL Tang Tao-Tao TT Ni Wei-Jie WJ Li Zhong-Tang ZT Jiang Liang-Yun-Zi LY Wang Yao Y Zhou Xuan X Cao Jing-Yuan JY Yin Qing Q Jiang Wei W Zhao Ya-Jie YJ Gan Wei-Hua WH Zhang Ai-Qing AQ Li Zuo-Lin ZL Wen Yi Y Lv Lin-Li LL Liu Bi-Cheng BC Wang Bin B

International journal of biological sciences 20240212 5

Direct tubular injury caused by several medications, especially chemotherapeutic drugs, is a common cause of AKI. Inhibition or loss of cyclin-dependent kinase 12 (CDK12) triggers a transcriptional elongation defect that results in deficiencies in DNA damage repair, producing genomic instability in a variety of cancers. Notably, 10-25% of individuals developed AKI after treatment with a CDK12 inhibitor, and the potential mechanism is not well understood. Here, we found that CDK12 was downregulat ...[more]

PMID: 38481813

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Project description:BackgroundCyclin-dependent kinase 12 (CDK12) loss occurs in 3-7% of metastatic prostate cancer patients and is characterized by a genomic instability signature, but the clinical implications of CDK12 loss are not well established.ObjectiveTo determine the clinical course of patients with CDK12 mutant advanced prostate cancer compared with other genomic subtypes.Design, setting, and participantsA retrospective analysis of data from three academic medical centers, including 317 patients with advanced prostate cancer and prior next-generation sequencing from tumor tissue (n = 172) or circulating tumor DNA (n = 145), was performed. Forty-six patients had CDK12 mutations; 34 had biallelic CDK12 loss (79%).Outcome measurements and statistical analysisPatients were stratified by mutation status (CDK12, homologous recombination deficiency [HRD; BRCA1/2 and ATM], TP53, and other cohort). The Kaplan-Meier method was used to evaluate time to event outcomes: time to development of metastatic disease, time to development of castration resistance, and time to prostate-specific antigen (PSA) progression after first-line androgen receptor pathway inhibitor (ARPI) therapy in a patient subset.Results and limitationsThe median follow-up was 66.6 mo. Patients with CDK12 mutant prostate cancer exhibited shorter time to metastasis (median = 34.9 mo, p =  0.004) and development of castration-resistant disease (median = 32.7 mo, p <  0.001), compared with other genomic subtypes, with shorter time to PSA progression on first-line ARPI treatment of metastatic castration-resistant disease (median = 3.6 mo, p =  0.0219). CDK12 mutant patients did not have overall shorter time on treatment compared with other mutation subgroups, and CDK12 status did not demonstrate statistical significance in multivariate analysis. Limitations include variable center-dependent practice patterns and heterogeneity due to combining tumor and liquid biopsy data.ConclusionsOur data suggest that advanced prostate cancers harboring CDK12 mutations display aggressive clinical behavior, underscoring the need to fully delineate the molecular and clinical characteristics, and appropriate therapeutic approaches for distinct subtypes of advanced prostate cancers.Patient summaryIn this report, we evaluate the clinical characteristics and outcomes of patients with prostate cancer and CDK12 mutation in their tumors. These patients seem to have more aggressive disease, with more high-grade Gleason ≥8 cancers and shorter time to developing metastatic cancer. Cases of advanced CDK12-mutated prostate cancer may warrant consideration of therapy intensification or combination approaches.

Dataset Information

Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects.

Publications

Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects.

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