Nickel-Catalyzed Enantioconvergent Allenylic Amination of Allenols Activated by Hydrogen-Bonding Interaction with Methanol.

The ubiquitous nature of amines in drug compounds, bioactive molecules and natural products has fueled intense interest in their synthesis. Herein, we introduce a nickel-catalyzed enantioconvergent allenylic amination of methanol-activated allenols. This protocol affords a diverse array of functionalized allenylic amines in high yields and with excellent enantioselectivities. The synthetic potential of this method is demonstrated by employing bioactive amines as nucleophiles and conducting gram-scale reactions. Furthermore, mechanistic investigations and DFT calculations elucidate the role of methanol as an activator in the nickel-catalyzed reaction, facilitating the oxidative addition of the C-O bond of allenols through hydrogen-bonding interactions. The remarkable outcomes arise from a rapid racemization of allenols enabled by the nickel catalyst and from highly enantioselective dynamic kinetic asymmetric transformation of η3-alkadienylnickel intermediates.

Photoinduced Decatungstate Anion-Catalyzed 1,4-Difunctionalization of 1,3-Butadienes via C-H Activation.

This paper outlines an innovative three-component coupling strategy for the 1,4-difunctionalization of 1,3-butadiene, utilizing sodium decatungstate (NaDT) as a hydrogen atom transfer (HAT) photocatalyst. The photoinduced process efficiently generates homoallylic amino acid esters with 100% atom economy, employing readily available components under mild reaction conditions. This light-induced protocol eliminates the need for an additional transition metal catalysts, additives, or equivalent reducing agents. The study explored various C(sp3)-H bearing partners, butadienes, and α-iminoesters, demonstrating the versatility and synthetic utility of this method.

Identification of cell surface markers for acute myeloid leukemia prognosis based on multi-model analysis.

Given the extremely high inter-patient heterogeneity among acute myeloid leukemia (AML), identifying biomarkers for prognostic assessment and therapeutic guidance is crucial. Cell surface markers (CSMs) have been shown to play an important role in AML leukemogenesis and progression. In this study, we evaluate the prognostic potential of all human CSMs in AML patients based on differential gene expression analysis and univariate Cox regression analysis. Utilizing multi-model analysis, including Adaptive LASSO regression, LASSO regression, and Elastic Net, we construct a 9-CSMs prognostic model for risk stratification of AML patients. The predictive value of the 9-CSMs risk score is further confirmed in three independent datasets. Multivariate Cox regression analysis shows that the risk score is an independent prognostic factor for AML patients. AML patients with high 9-CSMs risk scores have shorter overall and event-free survival time than those with lower scores. Notably, our single-cell RNA-seq analysis indicates that patients with high 9-CSMs risk scores exhibit chemotherapy resistance. Further, PI3K inhibitors are identified as potential treatments for these high-risk patients. In conclusion, we construct a 9-CSMs prognostic model which is an independent prognostic factor for the survival of AML patients and has the potential to guide drug therapy.

Low expression of miR-182 caused by DNA hypermethylation accelerates acute lymphocyte leukemia development by targeting PBX3 and BCL2: miR-182 promoter methylation is a predictive marker for hypomethylation agents + BCL2 inhibitor venetoclax.

BACKGROUND: miR-182 promoter hypermethylation frequently occurs in various tumors, including acute myeloid leukemia, and leads to low expression of miR-182. However, whether adult acute lymphocyte leukemia (ALL) cells have high miR-182 promoter methylation has not been determined. METHODS: To assess the methylation status of the miR-182 promoter, methylation and unmethylation-specific PCR analysis, bisulfite-sequencing analysis, and MethylTarget™ assays were performed to measure the frequency of methylation at the miR-182 promoter. Bone marrow cells were isolated from miR-182 knockout (182KO) and 182 wild type (182WT) mice to construct BCR-ABL (P190) and Notch-induced murine B-ALL and T-ALL models, respectively. Primary ALL samples were performed to investigate synergistic effects of the hypomethylation agents (HMAs) and the BCL2 inhibitor venetoclax (Ven) in vitro. RESULTS: miR-182 (miR-182-5P) expression was substantially lower in ALL blasts than in normal controls (NCs) because of DNA hypermethylation at the miR-182 promoter in ALL blasts but not in normal controls (NCs). Knockout of miR-182 (182KO) markedly accelerated ALL development, facilitated the infiltration, and shortened the OS in a BCR-ABL (P190)-induced murine B-ALL model. Furthermore, the 182KO ALL cell population was enriched with more leukemia-initiating cells (CD43+B220+ cells, LICs) and presented higher leukemogenic activity than the 182WT ALL population. Furthermore, depletion of miR-182 reduced the OS in a Notch-induced murine T-ALL model, suggesting that miR-182 knockout accelerates ALL development. Mechanistically, overexpression of miR-182 inhibited proliferation and induced apoptosis by directly targeting PBX3 and BCL2, two well-known oncogenes, that are key targets of miR-182. Most importantly, DAC in combination with Ven had synergistic effects on ALL cells with miR-182 promoter hypermethylation, but not on ALL cells with miR-182 promoter hypomethylation. CONCLUSIONS: Collectively, we identified miR-182 as a tumor suppressor gene in ALL cells and low expression of miR-182 because of hypermethylation facilitates the malignant phenotype of ALL cells. DAC + Ven cotreatment might has been applied in the clinical try for ALL patients with miR-182 promoter hypermethylation. Furthermore, the methylation frequency at the miR-182 promoter should be a potential biomarker for DAC + Ven treatment in ALL patients.

Low-dose hypomethylating agents cooperate with ferroptosis inducers to enhance ferroptosis by regulating the DNA methylation-mediated MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway in acute myeloid leukemia.

BACKGROUND: Ferroptosis is a new form of nonapoptotic and iron-dependent type of cell death. Glutathione peroxidase-4 (GPX4) plays an essential role in anti-ferroptosis by reducing lipid peroxidation. Although acute myeloid leukemia (AML) cells, especially relapsed and refractory (R/R)-AML, present high GPX4 levels and enzyme activities, pharmacological inhibition of GPX4 alone has limited application in AML. Thus, whether inhibition of GPX4 combined with other therapeutic reagents has effective application in AML is largely unknown. METHODS: Lipid reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH) assays were used to assess ferroptosis in AML cells treated with the hypomethylating agent (HMA) decitabine (DAC), ferroptosis-inducer (FIN) RAS-selective lethal 3 (RSL3), or their combination. Combination index (CI) analysis was used to assess the synergistic activity of DAC + RSL3 against AML cells. Finally, we evaluated the synergistic activity of DAC + RSL3 in murine AML and a human R/R-AML-xenografted NSG model in vivo. RESULTS: We first assessed GPX4 expression and found that GPX4 levels were higher in AML cells, especially those with MLL rearrangements, than in NCs. Knockdown of GPX4 by shRNA and indirect inhibition of GPX4 enzyme activity by RSL3 robustly induced ferroptosis in AML cells. To reduce the dose of RSL3 and avoid side effects, low doses of DAC (0.5 µM) and RSL3 (0.05 µM) synergistically facilitate ferroptosis by inhibiting the AMP-activated protein kinase (AMPK)-SLC7A11-GPX4 axis. Knockdown of AMPK by shRNA enhanced ferroptosis, and overexpression of SLC7A11 and GPX4 rescued DAC + RSL3-induced anti-leukemogenesis. Mechanistically, DAC increased the expression of MAGEA6 by reducing MAGEA6 promoter hypermethylation. Overexpression of MAGEA6 induced the degradation of AMPK, suggesting that DAC inhibits the AMPK-SLC7A11-GPX4 axis by increasing MAGEA6 expression. In addition, DAC + RSL3 synergistically reduced leukemic burden and extended overall survival compared with either DAC or RSL3 treatment in the MLL-AF9-transformed murine model. Finally, DAC + RSL3 synergistically reduced viability in untreated and R/R-AML cells and extended overall survival in two R/R-AML-xenografted NSG mouse models. CONCLUSIONS: Our study first identify vulnerability to ferroptosis by regulating MAGEA6-AMPK-SLC7A11-GPX4 signaling pathway. Combined treatment with HMAs and FINs provides a potential therapeutic choice for AML patients, especially for R/R-AML.

Unraveling the molecular mechanisms driving enhanced invasion capability of extravillous trophoblast cells: a comprehensive review.

Precise extravillous trophoblast (EVT) invasion is crucial for successful placentation and pregnancy. This review focuses on elucidating the mechanisms that promote heightened EVT invasion. We comprehensively summarize the pivotal roles of hormones, angiogenesis, hypoxia, stress, the extracellular matrix microenvironment, epithelial-to-mesenchymal transition (EMT), immunity, inflammation, programmed cell death, epigenetic modifications, and microbiota in facilitating EVT invasion. The molecular mechanisms underlying enhanced EVT invasion may provide valuable insights into potential pathogenic mechanisms associated with diseases characterized by excessive invasion, such as the placenta accreta spectrum (PAS), thereby offering novel perspectives for managing pregnancy complications related to deficient EVT invasion.

Erratum: SPOP targets oncogenic protein ZBTB3 for destruction to suppress endometrial cancer.

[This corrects the article on p. 2797 in vol. 9, PMID: 31911863.].

The association between metacognition, coping style and fear of cancer recurrence among postmastectomy patients: A cross sectional study.

PURPOSE: To investigate the incidence of fear of cancer recurrence (FCR) in Chinese postmastectomy patients and explore the relationships between metacognition, coping style, and FCR on the basis of the self-regulating executive function model. METHODS: A total of 480 postmastectomy patients from two tertiary comprehensive hospitals in Xi'an were enrolled from March 2021 to November 2021. The participants completed demographic information, the Metacognitions Questionnaire-30 (MCQ-30), Positive Metacognitions and Positive Meta-Emotions Questionnaire (PMCEQ), Simplified Copying Style Questionnaire (SCSQ), and Fear of Cancer Recurrence Inventory Short Form (FCRI-SF). RESULTS: 34.2% of the respondents had scores indicating a clinical level of FCR (FCRI-SF≥13). FCR had a positive correlation with maladaptive metacognition and negative coping style (P < 0.01), while adaptive metacognition and positive coping style were negatively correlated (P < 0.01). Besides, maladaptive metacognition had both direct and indirect effects on FCR, with the indirect effect primarily mediated by negative coping style (total effect, 0.430). Adaptive metacognition had both direct and indirect effects on FCR, with the indirect effect primarily mediated by positive coping style (total effect,ï¹£0.302). CONCLUSION: FCR was a common phenomenon in postmastectomy patients and moderate in most patients. In addition, both metacognition and coping style had a direct and indirect association with the occurrence and development of FCR. Moreover, adaptive metacognition and maladaptive metacognition had different mechanisms on FCR in patients with breast cancer.

A meta-analysis of treatment for early-stage cervical cancer: open versus minimally invasive radical trachelectomy.

BACKGROUND: In previous systematic reviews, meta-analysis was lacking, resulting in the statistical difference between the data of different surgeries being impossible to judge. This meta-analysis aims to contrast the fertility results and cancer outcomes between open and minimally invasive surgery. METHOD: We systematically searched databases including PubMed, Embase, Cochrane, and Scopus to collect studies that included open and minimally invasive radical trachelectomy. A random-effect model calculated the weighted average difference of each primary outcome via Review Manager V.5.4. RESULT: Eight studies (1369 patients) were incorporated into our study. For fertility results, the Open group excels MIS group in pregnancies-Third trimester delivery [OR = 2.68; 95% CI (1.29, 5.59); P = 0.008]. Nevertheless, there is no statistical difference in clinical pregnancy, miscarriage, and second-trimester rate. Concerning cancer outcomes, no difference was detected in the overall survival [OR = 1.56; 95% CI (0.70, 3.45); P = 0.27] and recurrence [OR = 0.63; 95% CI (0.35, 1.12); P = 0.12]. Concerning surgery-related outcomes, the comprehensive effects revealed that the estimated blood loss of the Open group was higher than that of the MIS group[MD = 139.40; 95% CI (79.05, 199.75); P < 0.0001]. However, there was no difference between the postoperative complication rate in the two groups [OR = 1.52; 95% CI (0.89, 2.60); P = 0.12]. CONCLUSION: This meta-analysis suggested that the fertility result of the Open group may be better than the MIS group, while the MIS group has better surgery-related outcomes. Owing to the poor cases of our study, a more robust conclusion requires more relevant articles in the future. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022352999.

Protective effects of yeast extract against alcohol-induced liver injury in rats.

Oxidative stress, inflammatory response, and gut-liver axis dysbiosis have been suggested as the primarily involved in the pathogenesis of alcoholic liver injury. Previous research established that yeast extract (YE) has antioxidant, immune-boosting or microbiota-regulating properties. However, there is currently lack of information regarding the efficacy of YE on alcoholic liver injury. This study seeks to obtain data that will help to address this research gap using a Wistar male rat experimental model. Histologic and biochemical analysis results showed that the groups treated with both low-dose yeast extract (YEL) and high-dose yeast extract (YEH) had lower degrees of alcohol-induced liver injury. The abundance of Peptococcus and Ruminococcus reduced in the low-dose yeast extract (YEL) group, while that of Peptococcus, Romboutsia, Parasutterella, and Faecalibaculum reduced in the high-dose (YEH) group. Furthermore, Spearman analysis showed that the gut microbes were significantly associated with several liver-related indicators. For the analysis of differential metabolites and enriched pathways in the YEL group, the abundance of lysophosphatidylcholine (16:0/0:0) significantly increased, and then the levels of histamine, adenosine and 5' -adenine nucleotide were remarkedly elevated in the YEH group. These findings suggest that both high and low doses of YE can have different protective effects on liver injury in alcoholic liver disease (ALD) rats, in addition to improving gut microbiota disorder. Besides, high-dose YE has been found to be more effective than low-dose YE in metabolic regulation, as well as in dealing with oxidative stress and inflammatory responses.

Effects of a lymphedema prevention program based on the theory of knowledge-attitude-practice on postoperative breast cancer patients: A randomized clinical trial.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is one of the common postoperative complications that severely affects the functions of the arm and quality of life. Since lymphedema is difficult to treat and prone to recurrence, early prevention of lymphedema is crucial. METHODS: Patient diagnosed with breast cancer (N = 108) were randomized to the intervention (n = 52) or control group (n = 56). In the intervention group, patients were provided the lymphedema prevention program based on the theory of knowledge-attitude-practice during the perioperative period and the first three chemotherapy sessions (mainly includes health education, seminars, knowledge manuals, sports guidance, peer education, and WeChat group).The limb volume, handgrip strength, arm function, and quality of life were measured in all patients at the baseline, 9 weeks (T1), and 18 weeks (T2) after surgery. RESULTS: The incidence of lymphedema in the Intervention group was numerically lower than in the control group after implementing the lymphedema prevention program, but the difference was not statistically significant (T1: 1.9% vs. 3.8%, p = 1.000; T2: 3.6% vs. 7.1%, p = 0.744). However, compared with the control group, the intervention group showed there was less deterioration in handgrip strength (T1 [t = -2.512, p < 0.05] and T2 [t = -2.538, p < 0.05]), improved postoperative upper limb dysfunction (T1 [t = 3.087, p < 0.05] and T2 [t = 5.399, p < 0.05]) and less deterioration in quality of life (T1 [p < 0.05] and T2 [p < 0.05]). CONCLUSION: Although the investigated lymphedema prevention program improved arm function and quality of life, it did not reduce the incidence of lymphedema in postoperative breast cancer patients.

Quinoa Ameliorates Hepatic Steatosis, Oxidative Stress, Inflammation and Regulates the Gut Microbiota in Nonalcoholic Fatty Liver Disease Rats.

A long-term high-fat diet causes hepatic steatosis, which further leads to oxidative stress and inflammation. In this study, we firstly investigated the regulation effects of different amounts of quinoa on hepatic steatosis, oxidative stress, and inflammation of rats fed a high-fat diet, then the gut microbiota was dynamically determined. Sprague-Dawley (SD, male) rats were randomized into four groups: normal controls (NC, fed standard chow), model groups (HF, fed a high-fat diet), low quinoa intake (HF + LQ), and high quinoa intake (HF + HQ) groups, which were supplemented with 9% and 27% quinoa in the high-fat feed (equivalent to 100 g/day and 300 g/day human intake, respectively). The results showed that quinoa intake significantly inhibited the hepatomegaly and splenomegaly, ameliorated hepatic steatosis pathologically; effectively rescued the decrease in the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) and the increase in malondialdehyde (MDA). The levels of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), transforming growth factor-ß (TGF-ß), and leptin in rats of two quinoa groups were close to those of the NC group. Besides, high quinoa intake significantly increased the relative abundance of Akkermansia, and low quinoa intake significantly increased the relative abundance of Blautia at the genus level. The relative abundances of Blautia and Dorea in rats in the HF + HQ group were lower than those in rats in the HF + LQ group. In addition, the relative abundances of Clostridium and Turicibacter of rats in the two quinoa intervention groups were lower than those of rats in the HF group after 12 weeks of intervention. In summary, quinoa exhibits a series of beneficial effects in the prevention of nonalcoholic fatty liver disease (NAFLD) and is suggested to be a component of a daily diet for the prevention of NAFLD.

DNA hypermethylation-induced miR-182 silence targets BCL2 and HOXA9 to facilitate the self-renewal of leukemia stem cell, accelerate acute myeloid leukemia progression, and determine the sensitivity of BCL2 inhibitor venetoclax.

Rationale: microRNAs (miRNAs) are frequently deregulated and play important roles in the pathogenesis and progression of acute myeloid leukemia (AML). miR-182 functions as an onco-miRNA or tumor suppressor miRNA in the context of different cancers. However, whether miR-182 affects the self-renewal of leukemia stem cells (LSCs) and normal hematopoietic stem progenitor cells (HSPCs) is unknown. Methods: Bisulfite sequencing was used to analyze the methylation status at pri-miR-182 promoter. Lineage-negative HSPCs were isolated from miR-182 knockout (182KO) and wild-type (182WT) mice to construct MLL-AF9-transformed AML model. The effects of miR-182 depletion on the overall survival and function of LSC were analyzed in this mouse model in vivo. Results: miR-182-5p (miR-182) expression was lower in AML blasts than normal controls (NCs) with hypermethylation observed at putative pri-miR-182 promoter in AML blasts but unmethylation in NCs. Overexpression of miR-182 inhibited proliferation, reduced colony formation, and induced apoptosis in leukemic cells. In addition, depletion of miR-182 accelerated the development and shortened the overall survival (OS) in MLL-AF9-transformed murine AML through increasing LSC frequency and self-renewal ability. Consistently, overexpression of miR-182 attenuated AML development and extended the OS in the murine AML model. Most importantly, miR-182 was likely dispensable for normal hematopoiesis. Mechanistically, we identified BCL2 and HOXA9 as two key targets of miR-182 in this context. Most importantly, AML patients with miR-182 unmethylation had high expression of miR-182 followed by low protein expression of BCL2 and resistance to BCL2 inhibitor venetoclax (Ven) in vitro. Conclusions: Our results suggest that miR-182 is a potential therapeutic target for AML patients through attenuating the self-renewal of LSC but not HSPC. miR-182 promoter methylation could determine the sensitivity of Ven treatment and provide a potential biomarker for it.

Corylin inhibits the progression of Non-small cell lung cancer cells by regulating NF-κB signaling pathway via targeting p65.

BACKGROUND: Lung cancer is characterized by high-risk and high mortality, among which non-small cell lung cancer (NSCLC) conquers a dominant position. Previous studies have reported that corylin has anti-inflammatory, anti-oxidant, and anti-tumor effects; however, its role in NSCLC cells remains unclear. HYPOTHESIS: Corylin inhibits the progression of NSCLC cells. METHODS: A lentivector NF-κB luciferase reporter was constructed by molecular cloning. Corylin was screened and identified as an NF-κB pathway inhibitor by luciferase reporter assay. Corylin inhibited the expression of NF-κB downstream genes, which was detected by qRT-PCR. The effect of corylin on NSCLC cells was detected by colony formation assay, cell apoptosis, cell proliferation, in vitro invasion, and cell scratch assay. Corylin inhibited p65 nuclear translocation and was detected by molecular docking, immunofluorescence assay, and Western blot analysis. RESULTS: We constructed a lentiviral expression vector, containing an NF-κB luciferase reporter and established a stable A549 cell line for its expression. Using this cell line, corylin was screened and identified as an NF-κB pathway inhibitor. It was found that corylin inhibited the expression of NF-κB downstream genes and inhibited the proliferation and migration of NSCLC cells. Meanwhile, it was also found that corylin significantly reversed the increased proliferation of NSCLC cell lines induced by p65 overexpression. Molecular docking analysis showed that corylin could bind to p65 by hydrogen bonding. Further study showed that corylin inhibited the NF-κB signaling pathway by blocking p65 nuclear translocation. CONCLUSIONS: Our study screened and identified corylin as an NF-κB inhibitor and elucidated the molecular mechanism by which corylin inhibits the growth of NSCLC cells. The present study provides a novel strategy for improving the prognosis and treatment of NSCLC patients.

Pharmacological Activity of Quercetin: An Updated Review.

Quercetin, a natural flavonoid compound with a widespread occurrence throughout the plant kingdom, exhibits a variety of pharmacological activities. Because of the wide spectrum of health-promoting effects, quercetin has attracted much attention of dietitians and medicinal chemists. An updated review of the literature on quercetin was performed using PubMed, Embase, and Science Direct databases. This article presents an overview of recent developments in pharmacological activities of quercetin including anti-SARS-CoV-2, antioxidant, anticancer, antiaging, antiviral, and anti-inflammatory activities as well as the mechanism of actions involved. The biological activities of quercetin were evaluated both in vitro and in vivo, involving a number of cell lines and animal models, but metabolic mechanisms of quercetin in the human body are not clear. Therefore, further large sample clinical studies are needed to determine the appropriate dosage and form of quercetin for the treatment of the disease.

Research Progress on G-Quadruplexes in Human Telomeres and Human Telomerase Reverse Transcriptase (hTERT) Promoter.

The upregulation telomerase activity is observed in over 85-90% of human cancers and provides an attractive target for cancer therapies. The high guanine content in the telomere DNA sequences and the hTERT promoter can form G-quadruplexes (G4s). Small molecules targeting G4s in telomeres and hTERT promoter could stabilize the G4s and inhibit hTERT expression and telomere extension. Several G4 ligands have shown inhibitory effects in cancer cells and xenograft mouse models, indicating these ligands have a potential for cancer therapies. The current review article describes the concept of the telomere, telomerase, and G4s. Moreover, the regulation of telomerase and G4s in telomeres and hTERT promoter is discussed as well. The summary of the small molecules targeting G4s in telomeric DNA sequences and the hTERT promoter will also be shown.

Gender Differences in Excessive Screen Time among Chinese High School Students in Henan Province.

In a technology-driven society, adolescents are particularly vulnerable to the effects of excessive screen time, and gender disparities are notable. However, evidence on the gender difference in excessive screen time among Chinese high school students is scarce. This study examined gender differences in excessive screen time and its impact on mental health and urinary incontinence among 15,055 high school-aged adolescents, including 7514 (49.9%) males and 7541 (50.1%) females with the mean age of 16.72 (SD 0.88) in Henan Province, China. A stratified two-stage cluster sampling design was applied. Mental Health Inventory of Middle School Students and International Consultation on Incontinence Questionnaire-Short Form was used to collect data about mental health and urinary incontinence status. The percentage of students reporting excessive screen time was 9.4%, predominantly male (15.3% versus 3.5%; p < 0.001). Physical disease, living on campus, and cigarette or alcohol consumption were common factors associated with excessive screen time in both genders. Students in their second or third year showed significantly lower rates of excessive screen time than their peers. In males, younger age, active sexual behavior, chronic constipation, and having a mother with a Ph.D. degree were factors associated with a higher probability of reporting excessive screen time, while females living in a rural-urban continuum or whose mothers have a junior college degree were associated with higher odds of reporting excessive screen times. Excessive screen time was significantly positively correlated with mental health problems and urinary incontinence (p < 0.05). Results suggests the need to address excessive screen time and to focus separately on the mechanisms influencing excessive screen time in males and females.

Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP-HIPK2 axis.

Speckle-type Poz protein (SPOP), an E3 ubiquitin ligase adaptor, is the most frequently mutated gene in prostate cancer. The SPOP-mutated subtype of prostate cancer shows high genomic instability, but the underlying mechanisms causing this phenotype are still largely unknown. Here, we report that upon DNA damage, SPOP is phosphorylated at Ser119 by the ATM serine/threonine kinase, which potentiates the binding of SPOP to homeodomain-interacting protein kinase 2 (HIPK2), resulting in a nondegradative ubiquitination of HIPK2. This modification subsequently increases the phosphorylation activity of HIPK2 toward HP1γ, and then promotes the dissociation of HP1γ from trimethylated (Lys9) histone H3 (H3K9me3) to initiate DNA damage repair. Moreover, the effect of SPOP on the HIPK2-HP1γ axis is abrogated by prostate cancer-associated SPOP mutations. Our findings provide new insights into the molecular mechanism of SPOP mutations-driven genomic instability in prostate cancer.

Erratum: SPOP targets oncogenic protein ZBTB3 for destruction to suppress endometrial cancer.

[This corrects the article on p. 2797 in vol. 9, PMID: 31911863.].