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

BACKGROUND: Cyclin-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. METHODS: Based 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. RESULTS: CDK12-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. CONCLUSIONS: Our 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.

YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent ferroptosis suppression in lung cancer.

Ferroptosis is a regulated cell death process initiated by iron-dependent phospholipid peroxidation and is mainly suppressed by GPX4-dependent and FSP1-dependent surveillance mechanisms. However, how the ferroptosis surveillance system is regulated during cancer development remains largely unknown. Here, we report that the YTHDC1-mediated m6A epigenetic regulation of FSP1 alleviates the FSP1-dependent ferroptosis suppression that partially contributes to the tumor suppressive role of YTHDC1 in lung cancer progression. YTHDC1 knockdown promoted the lung tumor progression and upregulated FSP1 protein level that resulted in ferroptosis resistance of lung cancer cells. Silencing FSP1 abrogated YTHDC1 knockdown-induced proliferation increase and ferroptosis resistance. Mechanistically, YTHDC1 binding to the m6A sites in the FSP1 3'-UTR recruited the alternative polyadenylation regulator CSTF3 to generate a less stable shorter 3'-UTR contained FSP1 mRNA, whereas YTHDC1 downregulation generated the longer 3'-UTR contained FSP1 mRNA that is stabilized by RNA binding protein HuR and thus led to the enhanced FSP1 protein level. Therefore, our findings identify YTHDC1 as a tumor progression suppressor in lung cancer and a ferroptosis regulator through modulating the FSP1 mRNA stability and thus suggest a ferroptosis-related therapeutic option for YTHDC1high lung cancer.

Association between occupational noise exposure duration and heart rate variability among Chinese adults: The role of plasma miRNAs.

We aimed to explore the association between occupational noise exposure duration and heart rate variability (HRV) and the underlying mechanism. A total of 449 subjects in a manufacturing company in Wuhan, China were included in our study and six candidate miRNAs (miR-200a-3p, miR-200b-3p, miR-200c-3p, miR-1-3p, miR-92a-3p and miR-21-5p) were tested among 200 individuals. Information combining the work histories and the occupational noise monitoring records were used to calculate the exposure of occupational noise, HRV indices were measured by using 3-channel digital Holter monitors, including the standard deviation of all normal R-R intervals (SDNN), the root mean of the square of successive differences between adjacent normal NN intervals (r-MSSD), SDNN index, low-frequency power (LF), high-frequency power (HF) and TP (total power). We found a significant linear negative dose-response relationship between occupational noise exposure duration and HRV indices (P for overall <0.05, P for nonlinear >0.05), including SDNN, r-MSSD, SDNN index, LF and HF. In the continuous models, the ß (95% CIs) for each 1-year occupational noise exposure were -0.002 (-0.004, -0.001) for SDNN, -0.002 (-0.004, -0.001) for r-MSSD, -0.002 (-0.004, -0.001) for SDNN index, and -0.006 (-0.012, -0.001) for HF. Meanwhile, we also found that occupational noise exposure duration was significantly associated with lower expression of five miRNAs, when adjusting for other covariates. The ß (95% CIs) were -0.039 (-0.067, -0.011) for miRNA-200c-3p, -0.053 (-0.083, -0.022) for miRNA-200a-3p, -0.044 (-0.070, -0.019) for miRNA-200b-3p, -0.032 (-0.048, -0.017) for miRNA-92a-3p, and -0.063 (-0.089, -0.038) for miRNA-21-5p in the continuous models. In addition, we found a positive association between miRNA-1-3p and LF (ß = 0.039, 95% CI = 0.002, 0.080). Our study suggests that occupational noise exposure duration is associated with cardiac autonomic dysfunction, and the role of miRNAs in noise induced HRV reduction needs to be confirmed in future studies.

A potassium-chloride co-transporter promotes tumor progression and castration resistance of prostate cancer through m6A reader YTHDC1.

SLC12A5, a neuron-specific potassium-chloride co-transporter, has been reported to promote tumor progression, however, the underlying mechanism remains unclear. Here we report that SLC12A5 functions as an oncogene to promote tumor progression and castration resistance of prostate cancer through the N6-methyladenosine (m6A) reader YTHDC1 and the transcription factor HOXB13. We have shown that the level of SLC12A5 was increased in prostate cancer, in comparison to its normal counterparts, and further elevated in castration-resistant prostate cancer (CRPC). The enhanced expression of SLC12A5 mRNA was associated with neuroendocrine prostate cancer (NEPC) progression and poor survival in prostate cancer. Furthermore, we demonstrated that SLC12A5 promoted the castration resistance development of prostate cancer in addition to the cell proliferation and migration. Interestingly, SLC12A5 was detected in the cell nucleus and formed a complex with nuclear m6A reader YTHDC1, which in turn upregulated HOXB13 to promote the prostate cancer progression. Therefore, our findings reveal a mechanism that how the potassium-chloride cotransporter SLC12A5 promotes the tumor progression and provide a therapeutic opportunity for prostate cancer to apply the neurological disorder drug SLC12A5 inhibitors.

Androgen Metabolism and Response in Prostate Cancer Anti-Androgen Therapy Resistance.

All aspects of prostate cancer evolution are closely related to androgen levels and the status of the androgen receptor (AR). Almost all treatments target androgen metabolism pathways and AR, from castration-sensitive prostate cancer (CSPC) to castration-resistant prostate cancer (CRPC). Alterations in androgen metabolism and its response are one of the main reasons for prostate cancer drug resistance. In this review, we will introduce androgen metabolism, including how the androgen was synthesized, consumed, and responded to in healthy people and prostate cancer patients, and discuss how these alterations in androgen metabolism contribute to the resistance to anti-androgen therapy.

Iron decorated ultrathin cobaltous hydroxide nanoflakes with impressive electrochemical reactivity for aqueous Zn batteries.

The main bottlenecks of current Co-based cathodes are their relatively low capacity and inferior reversibility. Here, we report Fe decorated cobaltous hydroxide (FCO) nanoflakes with vastly improved capacity and cycling stability via an efficient surface activation approach, which function as an advanced cathode for Co-Zn batteries. In comparison with the pristine cobaltous hydroxide (CO), the FCO sample owns higher electrochemical reactivity and a larger electrochemical surface area, endowing it with impressive electrochemical properties.

[Chronic psychological stress exacerbates aortic medial calcification via glucocorticoids].

Chronic psychological stress can promote vascular diseases, such as hypertension and atherosclerosis. This study aims to explore the effects and mechanism of chronic psychological stress on aortic medial calcification (AMC). Rat arterial calcification model was established by nicotine gavage in combination with vitamin D3 (VitD3) intramuscular injection, and rat model of chronic psychological stress was induced by humid environment. Aortic calcification in rats was evaluated by using Alizarin red staining, aortic calcium content detection, and alkaline phosphatase (ALP) activity assay. The expression levels of the related proteins, including vascular smooth muscle cells (VSMCs) contractile phenotype marker SM22α, osteoblast-like phenotype marker RUNX2, and endoplasmic reticulum stress (ERS) markers (GRP78 and CHOP), were determined by Western blot. The results showed that chronic psychological stress alone induced AMC in rats, further aggravated AMC induced by nicotine in combination with VitD3, promoted the osteoblast-like phenotype transformation of VSMCs and aortic ERS activation, and significantly increased the plasma cortisol levels. The 11ß-hydroxylase inhibitor metyrapone effectively reduced chronic psychological stress-induced plasma cortisol levels and ameliorated AMC and aortic ERS in chronic psychological stress model rats. Conversely, the glucocorticoid receptor agonist dexamethasone induced AMC, promoted AMC induced by nicotine combined with VitD3, and further activated aortic ERS. The above effects of dexamethasone could be inhibited by ERS inhibitor 4-phenylbutyrate. These results suggest that chronic psychological stress can lead to the occurrence and development of AMC by promoting glucocorticoid synthesis, which may provide new strategies and targets for the prevention and control of AMC.

A quinone electrode with reversible phase conversion for long-life rechargeable aqueous aluminum-metal batteries.

The exploration of high-performance cathode candidates is of great significance for aqueous aluminum-metal batteries (AAMBs). Here, we, for the first time, report tetrachloro-1,4-benzoquinone (TCQ) as a superior organic AAMB cathode. Owing to its high reversible conversion between the carbonyl and hydroxyl groups, the TCQ cathode delivers a remarkable electrochemical performance.

Oxygen-Vacancy and Surface Modulation of Ultrathin Nickel Cobaltite Nanosheets as a High-Energy Cathode for Advanced Zn-Ion Batteries.

The development of high-capacity, Earth-abundant, and stable cathode materials for robust aqueous Zn-ion batteries is an ongoing challenge. Herein, ultrathin nickel cobaltite (NiCo2 O4 ) nanosheets with enriched oxygen vacancies and surface phosphate ions (P-NiCo2 O4-x ) are reported as a new high-energy-density cathode material for rechargeable Zn-ion batteries. The oxygen-vacancy and surface phosphate-ion modulation are achieved by annealing the pristine NiCo2 O4 nanosheets using a simple phosphating process. Benefiting from the merits of substantially improved electrical conductivity and increased concentration of active sites, the optimized P-NiCo2 O4-x nanosheet electrode delivers remarkable capacity (309.2 mAh g-1 at 6.0 A g-1 ) and extraordinary rate performance (64% capacity retention at 60.4 A g-1 ). Moreover, based on the P-NiCo2 O4-x cathode, our fabricated P-NiCo2 O4-x //Zn battery presents an impressive specific capacity of 361.3 mAh g-1 at the high current density of 3.0 A g-1 in an alkaline electrolyte. Furthermore, extremely high energy density (616.5 Wh kg-1 ) and power density (30.2 kW kg-1 ) are also achieved, which outperforms most of the previously reported aqueous Zn-ion batteries. This ultrafast and high-energy aqueous Zn-ion battery is promising for widespread application to electric vehicles and intelligent devices.