Outcome of regenerative endodontic procedures in delayed replanted immature permanent teeth with apical periodontitis: A retrospective study.

BACKGROUND: Regenerative endodontic procedures (REPs) is effective for treating young permanent teeth with pulp necrosis. However, its efficacy on delayed replanted avulsed teeth is unclear. AIM: This retrospective study aimed to assess the efficacy of REPs in treating delayed replanted immature permanent teeth with apical periodontitis. DESIGN: Avulsed teeth receiving REPs were systematically screened based on predetermined criteria. This study assessed the REP outcomes, postoperative periodontal healing, and overall treatment efficacy. Samples were grouped by REP outcomes and root development stage, with Fisher's exact tests used to compare outcomes among different groups. RESULTS: Among the included 17 teeth, 47.1% exhibited successful REPs and periodontal healing. Another 47.1%, due to replacement resorption or REP failure, were categorized as tooth survival. Healing of periapical lesions was observed in 88.2% of the cases, but only 41.2% demonstrated continued root development. Although differences were not significant (p = 0.05), teeth with continued root development had a higher rate of functional healing (85.7%) compared to those without (30%). CONCLUSION: Within the limitations of this study, REPs presented reliable outcomes for treating delayed replanted immature permanent teeth with apical periodontitis mainly in periapical lesion healing. Teeth with continued root development after REPs exhibited a higher rate of functional healing. Further investigation is required to explore potential synergies between REP outcomes and periodontal healing.

Docosahexaenoic acid insufficiency impairs placental angiogenesis by repressing the methylene-bridge fatty acylation of AKT in preeclampsia.

INTRODUCTION: Preeclampsia (PE), characterised by hypertension in pregnancy, is regarded as a placental metabolism-related syndrome affecting 5-8% of pregnancies worldwide. The insufficiency of polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), is a causative factor of PE pathogenesis. However, its molecular aetiology is yet to be comprehensively elucidated. METHODS: CRISPR/Cas9 was used to construct Fads2 knockout mice. Gas chromatography-mass spectrometry was used to detect placental fatty acid levels. Gene Expression Omnibus was used to analyze placental FADS2 mRNA levels. CCK-8 assay was used to assess cell growth capacity. Cell migration and invasion abilities were measured by transwell and wound healing assay. Tube forming assay was used to test angiogenesis ability. The co-immunoprecipitation assay was used to validate interactions between two proteins. AKT inhibitor MK-2206 and methylene-bridge fatty acylation inhibitor tryptophan were used to rescue experiments. RESULTS: Compared to those in women with normal pregnancies, the DHA levels in the placentas of patients with PE decreased with the downregulation of FADS2, the key desaturase in the synthesis of PUFAs. Pregnant Fads2+/- mice exhibited PE-like symptoms, including proteinuria and elevated systolic arterial blood pressure, due to defective placental angiogenesis. Mechanistically, FADS2 knockdown in trophoblasts decreased cellular DHA levels and repressed the methylene-bridge fatty-acylation of AKT, inhibiting AKT-VEGFA signalling, which is crucial for angiogenesis. DISCUSSION: Our results suggest that placental DHA insufficiency downregulates placental angiogenesis via inhibiting fatty acylating AKT and AKT-VEGFA signalling, a novel insight into abnormal fatty acid metabolism in PE.

OTU deubiquitinase, ubiquitin aldehyde binding 2 (OTUB2) modulates the stemness feature, chemoresistance, and epithelial-mesenchymal transition of colon cancer via regulating GINS complex subunit 1 (GINS1) expression.

BACKGROUND: Colon cancer is one of the most prevalent tumors in the digestive tract, and its stemness feature significantly contribute to chemoresistance, promote the epithelial-mesenchymal transition (EMT) process, and ultimately lead to tumor metastasis. Therefore, it is imperative for researchers to elucidate the molecular mechanisms underlying the enhancement of stemness feature, chemoresistance, and EMT in colon cancer. METHODS: Sphere-formation and western blotting assays were conducted to assess the stemness feature. Edu, flow cytometry, and cell viability assays were employed to evaluate the chemoresistance. Immunofluorescence and western blotting assays were utilized to detect EMT. Immunoprecipitation, ubiquitination, agarose gel electrophoresis, chromatin immunoprecipitation followed by quantitative PCR (chip-qPCR), and dual luciferase reporter gene assays were employed for mechanistic investigations. RESULTS: We demonstrated a markedly higher expression level of OTUB2 in colon cancer tissues compared to adjacent tissues. Furthermore, elevated OTUB2 expression was closely associated with poor prognosis and distant tumor metastasis. Functional experiments revealed that knockdown of OTUB2 attenuated stemness feature of colon cancer, enhanced its sensitivity to oxaliplatin, inhibited its EMT process, ultimately reduced the ability of tumor metastasis. Conversely, overexpression of OTUB2 exerted opposite effects. Mechanistically, we identified OTUB2 as a deubiquitinase for SP1 protein which bound specifically to SP1 protein, thereby inhibiting K48 ubiquitination of SP1 protein. The SP1 protein functioned as a transcription factor for the GINS1, exerting its regulatory effect by binding to the 1822-1830 region of the GINS1 promoter and enhancing its transcriptional activity. Ultimately, alterations in GINS1 expression directly regulated stemness feature, chemosensitivity, and EMT progression in colon cancer. CONCLUSION: Collectively, the OTUB2/SP1/GINS1 axis played a pivotal role in driving stemness feature, chemoresistance, and EMT in colon cancer. These results shed new light on understanding chemoresistance and metastasis mechanisms involved in colon cancer.

SULF1 regulates malignant progression of colorectal cancer by modulating ARSH via FAK/PI3K/AKT/mTOR signaling.

BACKGROUND: Colorectal cancer (CRC) has the third highest incidence and second mortality rate of malignant tumors globally, highlighting the urgency to explore the mechanisms underlying CRC progression for refined treatment of this patient population. METHODS: R Studio was used for data sorting and analysis. Cell apoptosis and cell cycle detection were performed by flow cytometry. Quantitative real-time PCR (qRT-PCR) was used to explore mRNA expression levels. Western blotting was used to explore protein expression levels. CCK8, EdU, and colony formation assays were performed to explore the proliferation capacity of CRC cells. Transwell invasion and migration assays, along with the wound healing assay, were used to explore the invasive and migratory abilities of CRC cells. Subcutaneous Xenograft Assay was utilized to evaluate the tumorigenic capacity of CRC cells in vivo. RESULTS: SULF1 was highly expressed in CRC samples and cell lines. The knockdown of SULF1 inhibited the proliferation, invasion, and migration of CRC and increased the rate of cell apoptosis. Meanwhile, we demonstrated that SULF1 could negatively regulate ARSH through the FAK/PI3K/AKT/mTOR pathway. CONCLUSION: We demonstrated that SULF1 could promote CRC progression by regulating ARSH. The SULF1/ARSH/FAK/PI3K/AKT/mTOR signaling pathway represents a promising target for the treatment of this patient population. Colorectal cancer (CRC) has the third highest incidence and second mortality rate of malignant tumors globally. Sulfatase 1 (SULF1) belongs to the sulfatase family, The function of SULF1 in CRC remains elusive. Our study demonstrated that the knockdown of SULF1 could inhibit the proliferation, invasion, and migration of CRC. Meanwhile, our findings indicated that SULF1 could interact with Arylsulfatase Family Member H (ARSH) to regulate the proliferation, invasion, and migration of CRC via the FAK/PI3K/AKT/mTOR signaling pathway. Taken together, our findings suggest that SULF1 might be a new therapeutic target in CRC.

Chemokine­ and chemokine receptor-based subtypes predict prognosis, immunotherapy and chemotherapy response in colorectal cancer patients.

BACKGROUND: The clinical significance and comprehensive characteristics of chemokines and chemokine receptors in colorectal cancer (CRC) have not been previously reported. Our study aims to investigate the expression profiles of chemokines and chemokine receptors, as well as establish subtypes in CRC. METHODS: 1009 CRC samples were enrolled in our study. Consensus unsupervised clustering analysis was conducted to establish subtypes, and a risk score model was developed using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analyses. 36 pairs of tissue specimens of CRC patients and two CRC cell lines were used to validate the subtypes and risk score in vitro. Quantitative real-time PCR and western blotting were employed to validate mRNA and protein expression levels, respectively. Flow cytometry was utilized for analyzing cell apoptosis, while cell viability assay and EdU assay were conducted to assess cell proliferation ability. RESULTS: The Cluster B group shares similarities with the low-risk group in terms of exhibiting a higher level of immune cell infiltration and belonging to hot tumor. Patients CRC in the Cluster B group demonstrate a more favorable prognosis and exhibit better response to immunotherapy and chemotherapy. On the other hand, the Cluster A group resembles the high-risk group as it displays lower levels of immune cell infiltration, indicating a cold tumor phenotype. CRC patients in the Cluster A group have poorer prognoses and show less therapeutic efficacy towards immunotherapy and chemotherapy. Furthermore, we utilized a total of 36 pairs of tissue samples obtained from patients with CRC, along with two CRC cell lines for validation in vitro. This comprehensive approach further enhances the scientific validity and reliability of the identified subtypes and risk score in their ability to predict prognosis, response to immunotherapy, and response to chemotherapy among CRC patients. CONCLUSION: We first established robust prognostic subtypes based on chemokines and chemokine receptors, which could potentially serve as a novel biomarker for guiding individualized treatment in patients with CRC undergoing immunotherapy and chemotherapy.

Initial [18F]DCFPyL PET/CT in treatment-naïve prostate cancer: correlation with post-ADT PSA outcomes and recurrence.

PURPOSE: Positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) targeting tracers has emerged as a valuable diagnostic tool for prostate cancer (PCa), androgen deprivation therapy (ADT) stands as the cornerstone treatment for advanced PCa, yet forecasting the response to hormonal therapy poses a significant clinical hurdle. METHODS: In a prospective cohort of 86 PCa patients undergoing short-term ADT, this study evaluated the prognostic potential of [18F]DCFPyL PET/CT scans. Comprehensive data encompassing clinical profiles, baseline prostate-specific antigen (PSA) levels, and imaging metrics were assessed. We developed predictive models for assessing decreases in PSA levels (PSA50 and PSA70) based on a combination of PET-related parameters and clinical factors. Kaplan-Meier survival analysis was utilized to ascertain the prognostic value of PET-based metrics. RESULTS: In this study, elevated [18F]DCFPyL uptake within the primary tumor, as indicated by a SUV ≥ 6.78 (p = 0.0024), and a reduction in the tumor volume (TV) of primary PSMA-avid tumor with PSMA-TV < 41.96 cm3 (p = 0.038), as well as an increased burden of metastatic PSMA-avid tumor, with PSMA-TV (PSMA-TV ≥ 71.39 cm3) (p = 0.012) were identified in association with diminished progression-free survival (PFS). PET and clinical parameters demonstrated constrained predictive capacity for PSA50 response as indicated by an area under the curve (AUC) of 0.442. CONCLUSION: Our study revealed that pretreatment [18F]DCFPyL uptake in primary or metastatic tumor sites is prognostically relevant in high-risk PCa patients undergoing ADT. Further research is needed to develop robust predictive models in this multifaceted landscape of PCa management.

The evaluation of effective rate and pain intensity of root canal treatment in primary teeth-a retrospective study.

Two-visit root canal treatment for children reduce the time of visits and the by-chair time in comparison with the three-visit root canal treatment. However, it is not clear whether two-visit root canal treatment increase the risk of complications. This study aimed to evaluate the clinical effects and post-operative pain intensity after the root canal treatment between two-visit and three-visit groups in primary molars from children.106 patients were screened for eligibility, of which 74 went back to the preservation visit. Therefore, 74 primary molars from 74 children that diagnosed with chronic pulp and periodontal tissue diseases in the clinics of pediatric dentistry were retrospectively analyzed, in which 37 in the two-visit group and 37 in the three-visit group. The total effective rate and postoperative pain intensity were assessed after treatment and all statistical data were carried out with SPSS software.The average age of children in the two-visit and three-visit groups was 6.4 and 7.0, respectively, with no significant difference (p = 0.056). The two-visit group consisted of 59.5% male and 40.5% female children, while the three-visit group consisted of 56.8% male children and 43.2% female children (p = 0.813). Two months after treatment, the total effective rate in the three-visit group was 97.30%, a little higher than that in the two-visit group (94.59%), but with no significant difference (p = 0.201). Besides, there was also no significant difference in pain intensity between the two-visit and three-visit groups (p = 0.692). Therefore, there were no significant difference of total effective rate and pain intensity in root canal treatment between the two-visit and three-visit groups in primary molars from children.

The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer.

Lactylation has been recently identified as a new type of posttranslational modification occurring widely on lysine residues of both histone and nonhistone proteins. The acetyltransferase p300 is thought to mediate protein lactylation, yet the cellular concentration of the proposed lactyl-donor, lactyl-coenzyme A, is about 1,000 times lower than that of acetyl-CoA, raising the question of whether p300 is a genuine lactyltransferase. Here, we report that alanyl-tRNA synthetase 1 (AARS1) moonlights as a bona fide lactyltransferase that directly uses lactate and ATP to catalyze protein lactylation. Among the candidate substrates, we focused on the Hippo pathway, which has a well-established role in tumorigenesis. Specifically, AARS1 was found to sense intracellular lactate and translocate into the nucleus to lactylate and activate the YAP-TEAD complex; and AARS1 itself was identified as a Hippo target gene that forms a positive-feedback loop with YAP-TEAD to promote gastric cancer (GC) cell proliferation. Consistently, the expression of AARS1 was found to be upregulated in GC, and elevated AARS1 expression was found to be associated with poor prognosis for patients with GC. Collectively, this work found AARS1 with lactyltransferase activity in vitro and in vivo and revealed how the metabolite lactate is translated into a signal of cell proliferation.

DDHD2, whose mutations cause spastic paraplegia type 54, enhances lipophagy via engaging ATG8 family proteins.

Hereditary spastic paraplegia (HSP) is a group of inherited neurodegenerative disorders characterized by progressive lower limb spasticity and weakness. One subtype of HSP, known as SPG54, is caused by biallelic mutations in the DDHD2 gene. The primary pathological feature observed in patients with SPG54 is the massive accumulation of lipid droplets (LDs) in the brain. However, the precise mechanisms and roles of DDHD2 in regulating lipid homeostasis are not yet fully understood. Through Affinity Purification-Mass Spectroscopy (AP-MS) analysis, we identify that DDHD2 interacts with multiple members of the ATG8 family proteins (LC3, GABARAPs), which play crucial roles in lipophagy. Mutational analysis reveals the presence of two authentic LIR motifs in DDHD2 protein that are essential for its binding to LC3/GABARAPs. We show that DDHD2 deficiency leads to LD accumulation, while enhanced DDHD2 expression reduces LD formation. The LC3/GABARAP-binding capacity of DDHD2 and the canonical autophagy pathway both contribute to its LD-eliminating activity. Moreover, DDHD2 enhances the colocalization between LC3B and LDs to promote lipophagy. LD·ATTEC, a small molecule that tethers LC3 to LDs to enhance their autophagic clearance, effectively counteracts DDHD2 deficiency-induced LD accumulation. These findings provide valuable insights into the regulatory roles of DDHD2 in LD catabolism and offer a potential therapeutic approach for treating SPG54 patients.

Ketogenic diet-produced ß-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy.

Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced ß-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.

Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation.

Oxidative phosphorylation (OXPHOS) consumes oxygen to produce ATP. However, the mechanism that balances OXPHOS activity and intracellular oxygen availability remains elusive. Here, we report that mitochondrial protein lactylation is induced by intracellular hypoxia to constrain OXPHOS. We show that mitochondrial alanyl-tRNA synthetase (AARS2) is a protein lysine lactyltransferase, whose proteasomal degradation is enhanced by proline 377 hydroxylation catalyzed by the oxygen-sensing hydroxylase PHD2. Hypoxia induces AARS2 accumulation to lactylate PDHA1 lysine 336 in the pyruvate dehydrogenase complex and carnitine palmitoyltransferase 2 (CPT2) lysine 457/8, inactivating both enzymes and inhibiting OXPHOS by limiting acetyl-CoA influx from pyruvate and fatty acid oxidation, respectively. PDHA1 and CPT2 lactylation can be reversed by SIRT3 to activate OXPHOS. In mouse muscle cells, lactylation is induced by lactate oxidation-induced intracellular hypoxia during exercise to constrain high-intensity endurance running exhaustion time, which can be increased or decreased by decreasing or increasing lactylation levels, respectively. Our results reveal that mitochondrial protein lactylation integrates intracellular hypoxia and lactate signals to regulate OXPHOS.

Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation.

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. Inadequate understanding of the ovulation drivers hinders PCOS intervention. Herein, we report that follicle stimulating hormone (FSH) controls follicular fluid (FF) glutamine levels to determine ovulation. Murine ovulation starts from FF-exposing granulosa cell (GC) apoptosis. FF glutamine, which decreases in pre-ovulation porcine FF, elevates in PCOS patients FF. High-glutamine chow to elevate FF glutamine inhibits mouse GC apoptosis and induces hormonal, metabolic, and morphologic PCOS traits. Mechanistically, follicle-development-driving FSH promotes GC glutamine synthesis to elevate FF glutamine, which maintain follicle wall integrity by inhibiting GC apoptosis through inactivating ASK1-JNK apoptotic pathway. FSH and glutamine inhibit the rapture of cultured murine follicles. Glutamine removal or ASK1-JNK pathway activation with metformin or AT-101 reversed PCOS traits in PCOS models that are induced with either glutamine or EsR1-KO. These suggest that glutamine, FSH, and ASK1-JNK pathway are targetable to alleviate PCOS.

Tryptophanylation of insulin receptor by WARS attenuates insulin signaling.

Increased circulating amino acid levels have been linked to insulin resistance and development of type 2 diabetes (T2D), but the underlying mechanism remains largely unknown. Herein, we show that tryptophan modifies insulin receptor (IR) to attenuate insulin signaling and impair glucose uptake. Mice fed with tryptophan-rich chow developed insulin resistance. Excessive tryptophan promoted tryptophanyl-tRNA synthetase (WARS) to tryptophanylate lysine 1209 of IR (W-K1209), which induced insulin resistance by inhibiting the insulin-stimulated phosphorylation of IR, AKT, and AS160. SIRT1, but not other sirtuins, detryptophanylated IRW-K1209 to increase the insulin sensitivity. Collectively, we unveiled the mechanisms of how tryptophan impaired insulin signaling, and our data suggested that WARS might be a target to attenuate insulin resistance in T2D patients.

Chemokine- and chemokine receptor-based signature predicts immunotherapy response in female colorectal adenocarcinoma patients.

The clinical significance and comprehensive characteristics of chemokines and chemokine receptors in female patients with advanced colorectal adenocarcinoma have not ever been reported. Our study explored the expression profiles of chemokines and chemokine receptors and constructed a chemokine- and chemokine receptor-based signature in female patients with advanced colorectal adenocarcinoma. Four independent cohorts containing 1335 patients were enrolled in our study. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were performed to construct the signature. CIBERSORT was used to evaluate the landscape of immune cell infiltration. Thirty-two pairs of tissue specimens of female advanced colorectal cancer (CRC) patients and two CRC cell lines were used to validate the signature in vitro. Quantitative real-time PCR and western blotting were performed to validate the mRNA and protein expression levels of signature genes. EdU and colony formation assays were performed to examine proliferative ability. Transwell and wound healing assays were used to evaluate cell invasion and migration capacity. During the signature construction and validation process, we found that the signature was more applicable to female patients with advanced colorectal adenocarcinoma. Hence, the subsequent study mainly focused on the particular subgroup. Enrichment analyses revealed that the signature was closely related to immunity. The landscape of immune cell infiltration presented that the signature was significantly associated with T cells CD8 and neutrophils. Gene set enrichment analysis (GSEA) confirmed that the high-risk group was chiefly enriched in the tumor-promoting related pathways and biological processes, whereas the low-risk group was mainly enriched in anti-tumor immune response pathways and biological processes. The signature was closely correlated with CTLA4, PDL1, PDL2, TMB, MSI, and TIDE, indicating that our signature could serve as a robust biomarker for immunotherapy and chemotherapy response. ROC curves verified that our signature had more robust prognostic power than all immune checkpoints and immunotherapy-related biomarkers. Finally, we used 32 pairs of tissue specimens and 2 CRC cell lines to validate our signature in vitro. We first provided a robust prognostic chemokine- and chemokine receptor-based signature, which could serve as a novel biomarker for immunotherapy and chemotherapy response to guide individualized treatment for female patients with advanced colorectal adenocarcinoma.

Oral health-related quality of life and associated factors among a sample from East China with severe early childhood caries: a cross-sectional study.

BACKGROUND: To investigate the oral health-related quality of life (OHRQoL) and associated factors among a sample from East China with severe early childhood caries (S-ECC). METHODS: A total of 316 children with S-ECC and their parents were recruited to participate in a cross-sectional study. Children were examined for caries status using criteria proposed by World Health Organization (WHO). The accompanying parent was required to provide demographic information and complete two validated questionnaires in Chinese: the early childhood oral health impact scale (ECOHIS) and the 5-item oral health impact profile (OHIP). RESULTS: The study had a 98.1% response rate. Finally, the data of 300 children and their parents were analyzed. Mothers cared for their children far more than fathers in the included family (78.7% mother, 21.3% father). The mean age of children was 4.1 ± 0.7 years, ranging from 3 to 5. The mean dmft score was 13.8 ± 3.8. Few (13.7%) children never had a toothache. ECOHIS scores ranged from 0 to 38, with a mean score of 16.2 ± 7.2. The mean OHIP score was 2.9 ± 2.7. The parental age, family income, residence, history of pain, the dmft scores and parents' OHIP showed associations with ECOHIS scores or domain scores (P < 0.05). The multiple regression analysis showed that the history of pain, accompanying parents' OHIP, and the dmft scores were mainly associated with ECOHIS and child impact (P < 0.05); parental age was associated with family impact (P = 0.024). CONCLUSIONS: The parent's OHRQoL was associated with the children's OHRQoL, indicating that policymakers and clinical practitioners should improve both children's and their parents' oral health. Furthermore, the caries severity and the history of dental pain impacted children's OHRQoL.

m6A-Mediated Biogenesis of circDDIT4 Inhibits Prostate Cancer Progression by Sequestrating ELAVL1/HuR.

The pathologic significance of the circular RNA DDIT4 (circDDIT4), which is formed by backsplicing at the 3'-untranslated region (UTR) with a 5' splice acceptor site in exon 2 of linear DDIT4 mRNA, has yet to be determined. Our study found that circDDIT4 is downregulated in prostate cancer and functions as a tumor suppressor during prostate cancer progression. By competitively binding to ELAV-like RNA binding protein 1 (ELAVL1/HuR) through its 3'-UTR, circDDIT4 acts as a protein sponge to decrease the expression of prostate cancer-overexpressed anoctamin 7 (ANO7). This promotes prostate cancer cell apoptosis while inhibiting cell proliferation and metastasis. Furthermore, we discovered that N6-methyladenosine (m6A) modification facilitates the biogenesis of circDDIT4. The methyltransferase complex consisting of WTAP/METTL3/METTL14 increases the level of circDDIT4, while the RNA demethylase FTO decreases it. IMPLICATIONS: These findings suggest that abnormal cotranscriptional modification of m6A promotes prostate cancer initiation and progression via a circular RNA-protein-cell signaling network.