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

Haozhe Zhang1; Yi Zhou1; Yating Feng1; Wenli Hou2; Yafei Chen1; Zengzhen Xing1; Yifan Zhang2; Qiang Wei2; Yu Yin3; Ju Guo4; Hailiang Hu1,5

2024-04-17

10.1002/ctm2.1678

CLINICAL AND TRANSLATIONAL MEDICINE   影响因子和分区

2001-1326

["BackgroundCyclin-dependent kinase 12 (CDK12)-deficient prostate cancer defines a subtype of castration-resistant prostate cancer (CRPC) with a poor prognosis. Current therapy, including PARP inhibitors, shows minimal treatment efficacy for this subtype of CRPC, and the underlying mechanism remains elusive.MethodsBased on bioinformatics analysis, we evaluated the relationship between CDK12 deficiency and prostate cancer patient's prognosis and treatment resistance. Furthermore, we used CRISPR-Cas9 technology and mass spectrometry-based metabolomic profiling to reveal the metabolic characteristics of CDK12-deficient CRPC. To elucidate the specific mechanisms of CDK12 deficiency-mediated CRPC metabolic reprogramming, we utilized cell RNA-seq profiling and other molecular biology techniques, including cellular reactive oxygen species probes, mitochondrial function assays, ChIP-qPCR and RNA stability analyses, to clarify the role of CDK12 in regulating mitochondrial function and its contribution to ferroptosis. Finally, through in vitro drug sensitivity testing and in vivo experiments in mice, we identified the therapeutic effects of the electron transport chain (ETC) inhibitor IACS-010759 on CDK12-deficient CRPC.ResultsCDK12-deficient prostate cancers reprogramme cellular energy metabolism to support their aggressive progression. In particular, CDK12 deficiency enhanced the mitochondrial respiratory chain for electronic transfer and ATP synthesis to create a ferroptosis potential in CRPC cells. However, CDK12 deficiency downregulated ACSL4 expression, which counteracts the lipid oxidation stress, leading to the escape of CRPC cells from ferroptosis. Furthermore, targeting the ETC substantially inhibited the proliferation of CDK12-deficient CRPC cells in vitro and in vivo, suggesting a potential new target for the therapy of CDK12-deficient prostate cancer.ConclusionsOur findings show that energy and lipid metabolism in CDK12-deficient CRPC work together to drive CRPC progression and provide a metabolic insight into the worse prognosis of CDK12-deficient prostate cancer patients.Key points CDK12 deficiency promotes castration-resistant prostate cancer (CRPC) progression by reprogramming cellular metabolism. CDK12 deficiency in CRPC leads to a more active mitochondrial electron transport chain (ETC), ensuring efficient cell energy supply. CDK12 phosphorylates RNA Pol II to ensure the transcription of ACSL4 to regulate ferroptosis. Mitochondrial ETC inhibitors exhibit better selectivity for CDK12-deficient CRPC cells, offering a promising new therapeutic approach for this subtype of CRPC patients.","CDK12 deficiency reprograms prostate tumor cell metabolism, promotes tumor progression while demonstrating therapeutic targets. Identified the regulation of CDK12 on ACSL4 expression as a novel mechanism for controlling ferroptosis. image"]

CDK12 CRPC ferroptosis metabolism

SCI

英语

第一 ; 通讯

Oncology ; Research & Experimental Medicine

Oncology ; Medicine, Research & Experimental

WOS:001218610300001

JOHN WILEY & SONS LTD

人工提交

1.Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, China
2.Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China
3.Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
4.Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China
5.Key University Laboratory of Metabolism and Health of Guangdong, Southern University of Science and Technology, Shenzhen, China

Haozhe Zhang,Yi Zhou,Yating Feng,et al. Cyclin-dependent kinase 12 deficiency reprogrammes cellular metabolism to alleviate ferroptosis potential and promote the progression of castration-resistant prostate cancer[J]. CLINICAL AND TRANSLATIONAL MEDICINE,2024,14(5):e1678.

Haozhe Zhang.,Yi Zhou.,Yating Feng.,Wenli Hou.,Yafei Chen.,...&Hailiang Hu.(2024).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,14(5),e1678.

Haozhe Zhang,et al."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 14.5(2024):e1678.