Human molecular genetics最新文献

{"title":"Genome-wide association study of urinary cadmium levels in current smokers from the multiethnic cohort study.","authors":"Shannon M Sullivan, Sharon E Murphy, Daniel O Stram, Lynne R Wilkens, Christopher A Haiman, Loïc Le Marchand, Irina Stepanov, S Lani Park","doi":"10.1093/hmg/ddae202","DOIUrl":"10.1093/hmg/ddae202","url":null,"abstract":"<p><strong>Background: </strong>Cadmium (Cd), classified as an International Agency for Research on Cancer (IARC) Group 1 human carcinogen, is present in cigarette smoke. Recent studies have illustrated the potential role of genetics in influencing Cd biomarker levels.</p><p><strong>Methods: </strong>We conducted a genome-wide association study (GWAS) of urinary Cd levels in 1977 current smokers from the Multiethnic Cohort Study, comprising participants from five different racial and ethnic groups. Linear regression models were adjusted for age at urine collection, sex, self-reported race/ethnicity, and the top ten leading principal components.</p><p><strong>Results: </strong>Among the 11 710 497 single nucleotide polymorphisms (SNP) analyzed, no associations with urinary Cd reached genome-wide significance (P < 5.0 × 10-8). Notably, five variants demonstrated suggestive associations with urinary Cd levels (P < 1.0 × 10-6). Lead variants included: rs10097646 in the SCARA gene at 8q13.2 (P = 2.62 × 10-7); rs7444817 in the NIPBL gene at 5p13.2 (P = 3.10 × 10-7), rs830422 in the SPINK4 gene at 9q13.2 (P = 4.89 × 10-7); chrX:145489901 in the SLC9A7 gene at Xq121.1 (P = 5.38 × 10-7); and rs73074456 at 5p13.3 (P = 5.86 × 10-7).</p><p><strong>Conclusions: </strong>Our GWAS of urinary Cd levels in a diverse population of people who smoke, revealed suggestive associations with variants in SCARA5, NIPBL, SPINK4, SLC9A7, and 5p13.3. These findings underscore the potential role of genetic factors in understanding and mitigating the health risks associated with internal dose of carcinogens, particularly in the context of tobacco-related carcinogens.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"611-616"},"PeriodicalIF":3.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deregulated ion channels contribute to RHOBTB2-associated developmental and epileptic encephalopathy.","authors":"Franziska Langhammer, Anne Gregor, Niels R Ntamati, Arif B Ekici, Beate Winner, Thomas Nevian, Christiane Zweier","doi":"10.1093/hmg/ddae183","DOIUrl":"10.1093/hmg/ddae183","url":null,"abstract":"<p><p>While de novo missense variants in the BTB domains of atypical RhoGTPase RHOBTB2 cause a severe developmental and epileptic encephalopathy, de novo missense variants in the GTPase domain or bi-allelic truncating variants are associated with more variable neurodevelopmental and seizure phenotypes. Apart from the observation of RHOBTB2 abundance resulting from BTB-domain variants and increased seizure susceptibility in Drosophila overexpressing RhoBTB, our knowledge on RHOBTB2-related pathomechanisms is limited. We now found enrichment for ion channels among the differentially expressed genes from RNA-Seq on fly heads overexpressing RhoBTB. Subsequent genetic interaction experiments confirmed a functional link between RhoBTB and paralytic, the orthologue of human sodium channels, including epilepsy associated SCN1A, in vivo. We then performed patch-clamp recordings on mature neurons differentiated from human induced pluripotent stem cells with either homozygous frameshifts or patient-specific heterozygous missense variants in the GTPase or the BTB domains. This revealed significantly altered neuronal activity and excitability resulting from BTB domain variants but not from GTPase domain variants or upon complete loss of RHOBTB2. Our study indicates a role of deregulated ion channels in the pathogenesis of RHOBTB2-related developmental and epileptic encephalopathy and points to specific pathomechanisms underlying the observed genotype-phenotype correlations regarding variant zygosity, location and nature.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"639-650"},"PeriodicalIF":3.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Choroid plexus-targeted viral gene therapy for alpha-mannosidosis, a prototypical neurometabolic lysosomal storage disease.","authors":"Eun-Young Choi, John H Wolfe, Stephen G Kaler","doi":"10.1093/hmg/ddae201","DOIUrl":"10.1093/hmg/ddae201","url":null,"abstract":"<p><p>The choroid plexuses (CP) are highly vascularized structures that project into the ventricles of the vertebrate brain. The polarized epithelia of the CP produce cerebrospinal fluid by transporting water and ions into the ventricles from the blood and normally secrete a large number of proteins. We assessed the feasibility of selective CP transduction with recombinant adeno-associated virus (rAAV) gene therapy vectors for treatment of lysosomal storage disease (LSD), a broad category of neurometabolic illness associated with significant burdens to affected patients and their families. There are no ideal or complete therapeutic options currently available, especially for the central nervous system manifestations of LSDs. Alpha-mannosidosis (AMD) is an autosomal recessive prototypical LSD caused by deficiency of lysosomal alpha-mannosidase and characterized by cerebellar ataxia, neurocognitive disability, facial and skeletal abnormalities, hearing impairment, and mild immune deficiency. In a murine model of AMD, we compared the biochemical effects of CSF-directed rAAV serotypes 1, 4, 5, 6, and 9. Recombinant AAV1 and rAAV6, two closely related serotypes whose capsid sequences differ by only six amino acids, showed the most robust transduction of CP in mouse brain, consistent with their transduction of CPE in nonhuman primates and cats, as well as in other structures. We found restoration of LAMAN enzyme activity comparable to or higher than AMD heterozygote levels in the brain globally (olfactory bulb, cortex, cerebellum, brainstem). Further IND-generating preclinical experiments will advance rAAV6-LAMAN, which appears to be the most promising choroid plexus-targeting candidate serotype for future clinical translation to treat AMD.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"577-585"},"PeriodicalIF":3.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-canonical imprinting, manifesting as post-fertilization placenta-specific parent-of-origin dependent methylation, is not conserved in humans.","authors":"Dagne Daskeviciute, Louise Chappell-Maor, Becky Sainty, Philippe Arnaud, Isabel Iglesias-Platas, Carlos Simon, Hiroaki Okae, Takahiro Arima, Rita Vassena, Jon Lartey, David Monk","doi":"10.1093/hmg/ddaf009","DOIUrl":"10.1093/hmg/ddaf009","url":null,"abstract":"<p><p>Genomic imprinting is the parent-of-origin dependent monoallelic expression of genes often associated with regions of germline-derived DNA methylation that are maintained as differentially methylated regions (gDMRs) in somatic tissues. This form of epigenetic regulation is highly conserved in mammals and is thought to have co-evolved with placentation. Tissue-specific gDMRs have been identified in human placenta, suggesting that species-specific imprinting dependent on unorthodox epigenetic establishment or maintenance may be more widespread than previously anticipated. Non-canonical imprinting, reliant on differential allelic H3K27me3 enrichment, has been reported in mouse and rat pre-implantation embryos, often overlapping long terminal repeat (LTR)-derived promoters. These non-canonical imprints lose parental allele-specific H3K27me3 specificity, subsequently gaining DNA methylation on the same allele in extra-embryonic tissues resulting in placenta-specific, somatically acquired maternal DMRs. To determine if similar non-canonical imprinting is present in the human placenta, we interrogated allelic DNA methylation for a selected number of loci, including (i) the human orthologues of non-canonical imprinted regions in mouse and rat, (ii) promoters of human LTR-derived transcripts, and (iii) CpG islands with intermediate placenta-specific methylation that are unmethylated in gametes and pre-implantation embryos. We failed to identify any non-canonical imprints in the human placenta whole villi samples. Furthermore, the assayed genes were shown to be biallelically expressed in human pre-implantation embryos, indicating they are not imprinted at earlier time points. Together, our work reiterates the continued evolution of placenta-specific imprinting in mammals, which we suggest is linked to epigenetic differences during the maternal-to-embryo transition and species-specific integration of retrotransposable elements.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"626-638"},"PeriodicalIF":3.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are associated with increased risk of colorectal cancer.","authors":"Anna Prizment, Abby Standafer, Conghui Qu, Kathleen M Beutel, Shuo Wang, Wen-Yi Huang, Annika Lindblom, Rachel Pearlman, Bethany Van Guelpen, Alicja Wolk, Daniel D Buchanan, Robert C Grant, Stephanie L Schmit, Elizabeth A Platz, Corinne E Joshu, David J Couper, Ulrike Peters, Timothy K Starr, Patricia Scott, Nathan Pankratz","doi":"10.1093/hmg/ddaf007","DOIUrl":"10.1093/hmg/ddaf007","url":null,"abstract":"<p><strong>Background: </strong>Individuals with cystic fibrosis (CF; a recessive disorder) have an increased risk of colorectal cancer (CRC). Evidence suggests individuals with a single CFTR variant may also have increased CRC risk.</p><p><strong>Methods: </strong>Using population-based studies (GECCO, CORECT, CCFR, and ARIC; 53 785 CRC cases and 58 010 controls), we tested for an association between the most common CFTR variant (Phe508del) and CRC risk. For replication, we used whole exome sequencing data from UK Biobank (UKB; 5126 cases and 20 504 controls matched 4:1 based on genetic distance, age, and sex), and extended our analyses to all other heterozygous CFTR variants annotated as CF-causing.</p><p><strong>Results: </strong>In our meta-analysis of GECCO-CORECT-CCFR-ARIC, the odds ratio (OR) for CRC risk associated with Phe508del was 1.11 (P = 0.010). In our UKB replication, the OR for CRC risk associated with Phe508del was 1.28 (P = 0.002). The sequencing data from UKB also revealed an association between the presence of any other single CF-causing variant (excluding Phe508del) and CRC risk (OR = 1.33; P = 0.030). When stratifying CFTR variants by functional class, class I variants (no protein produced) had a stronger association (OR = 1.77; p = 0.002), while class II variants (misfolding and retention of the protein in the endoplasmic reticulum) other than Phe508del (OR = 1.75; p = 0.107) had similar effect size as Phe508del, and variants in classes III-VI had non-significant ORs less than 1.0 and/or were not present in cases.</p><p><strong>Conclusions: </strong>CF-causing heterozygous variants, especially class I variants, are associated with a modest but statistically significant increased CRC risk. More research is needed to explain the biology underlying these associations.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"617-625"},"PeriodicalIF":3.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory role of miR-128-2-5p in serum exosomes on COL6A2 expression and postmenopausal osteoporosis.","authors":"Liangjie Lu, Lijun Wang, Huihan Wang, Minjie Yang","doi":"10.1093/hmg/ddae147","DOIUrl":"10.1093/hmg/ddae147","url":null,"abstract":"<p><p>This study investigates the influence of miR-128-2-5p within serum-derived exosomes (Exos) on COL6A2 expression and its implications in postmenopausal osteoporosis (POMP). Utilizing bioinformatics analysis, we identified 1317 differentially expressed genes (DEGs), primarily enriched in the focal adhesion pathway-a critical regulator of osteoblast adhesion. A significant gene, COL6A2, emerged as notably downregulated in POMP, possessing potential as a diagnostic marker. Predictive analysis linked the upstream miRNA miR-128-2-5p, highly enriched in Exos, with the regulation of COL6A2. Experimentally, Exos from POMP patients demonstrated elevated miR-128-2-5p levels, which inhibited COL6A2 expression in vitro, reducing osteoblast adhesion and exacerbating osteoporotic conditions. These findings highlight the pivotal role of exosomal miR-128-2-5p in bone metabolism, suggesting a novel molecular mechanism and a potential therapeutic target in POMP.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"563-576"},"PeriodicalIF":3.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A de novo deletion underlying spinal muscular atrophy: implications for carrier testing and genetic counseling.","authors":"Maria M Zwartkruis, Mirjam S de Pagter, Demi Gommers, Marije Koopmans, Cecile P E Ottenheim, Joris V Kortooms, Mirjan Albring, Martin G Elferink, Renske I Wadman, Fay-Lynn Asselman, Inge Cuppen, W Ludo van der Pol, Marcel R Nelen, Gijs W van Haaften, Ewout J N Groen","doi":"10.1093/hmg/ddaf035","DOIUrl":"https://doi.org/10.1093/hmg/ddaf035","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is an autosomal recessive disease most commonly caused by homozygous deletion of the SMN1 gene. Parents of affected children are typically carriers, with a recurrence risk of 25% for future pregnancies. Their close relatives have up to 50% chance of being carriers. Carriers typically possess a single copy of the SMN1 gene; however, some parents carry two copies of SMN1. Current standard diagnostic carrier tests are unable to distinguish between silent carriers with two copies on one chromosome (2 + 0 genotype) and non-carriers (1 + 1 genotype), where a de novo deletion occurred. This distinction is crucial for recurrence risk assessment, which highlights the unsolved challenge to carrier testing and genetic counseling. We combined microsatellite marker analysis, SMN copy number analysis, Sanger sequencing, long-read sequencing and de novo assembly to investigate the cause of the absence of SMN1 in a pedigree with an SMA patient identified through newborn screening, whose parents each carried two SMN1 copies. Our analysis revealed that the father is a silent carrier, while de novo assembly of the SMN locus showed a 1.4 megabase (Mb) de novo deletion between mother and child. This deletion encompasses SMN1 and SMN2 and represents the first reported nucleotide-level resolved SMA-causing deletion to date. Our findings allowed informed counseling of at-risk relatives and illustrate the complexity of SMA carrier testing and counseling. This case underscores the feasibility of and need for advanced genetic testing for SMA carriership in select cases, to improve genetic counseling practices, risk assessment, and family planning.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aggregates associated with amyotrophic lateral sclerosis sequester the actin-binding protein profilin 2.","authors":"Sabrina Kubinski, Luisa Claus, Tobias Schüning, Andre Zeug, Norman Kalmbach, Selma Staege, Thomas Gschwendtberger, Susanne Petri, Florian Wegner, Peter Claus, Niko Hensel","doi":"10.1093/hmg/ddaf020","DOIUrl":"https://doi.org/10.1093/hmg/ddaf020","url":null,"abstract":"<p><p>Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of upper and lower motoneurons. The four most frequently mutated genes causing familial ALS (fALS) are C9orf72, FUS, SOD1, and TARDBP. Some of the related wild-type proteins comprise intrinsically disordered regions (IDRs) which favor their assembly in liquid droplets-the biophysical mechanism behind the formation of physiological granules such as stress granules (SGs). SGs assemble and dissolve dependent on the cellular condition. However, it has been suggested that transition from reversible SGs to irreversible aggregates contributes to the toxic properties of ALS-related mutated proteins. Sequestration of additional proteins within these aggregates may then result in downstream toxicity. While the exact downstream mechanisms remain elusive, rare ALS-causing mutations in the actin binding protein profilin 1 suggest an involvement of the actin cytoskeleton. Here, we hypothesize that profilin isoforms become sequestered in aggregates of ALS-associated proteins which induce subsequent dysregulation of the actin cytoskeleton. Interestingly, localization of neuronal profilin 2 in SGs was more pronounced compared with the ubiquitously expressed profilin 1. Accordingly, FUS and C9orf72 aggregates prominently sequestered profilin 2 but not profilin 1. Moreover, we observed a distinct sequestration of profilin 2 and G-actin to C9orf72 aggregates in different cellular models. On the functional level, we identified dysregulated actin dynamics in cells with profilin 2-sequestering aggregates. In summary, our results suggest a more common involvement of profilins in ALS pathomechanisms than indicated from the rarely occurring profilin mutations.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of CNBP in brain atrophy and its targeting in myotonic dystrophy type 2.","authors":"Katherine Jennings, Diana Lindquist, Ankita Poonia, Benedikt Schoser, Christiane Schneider-Gold, Nikolai A Timchenko, Lubov Timchenko","doi":"10.1093/hmg/ddaf002","DOIUrl":"10.1093/hmg/ddaf002","url":null,"abstract":"<p><p>Myotonic Dystrophy type 2 (DM2) is a multisystem disease affecting many tissues, including skeletal muscle, heart, and brain. DM2 is caused by unstable expansion of CCTG repeats in an intron 1 of a gene coding for cellular nuclear binding protein (CNBP). The expanded CCTG repeats cause DM2 pathology due to the accumulation of RNA CCUG repeats, which affect RNA processing in patients' cells. We have previously shown that mutant CCUG repeats reduce CNBP protein in DM2 patients. Reducing Cnbp in Cnbp KO mouse model causes late skeletal muscle atrophy. In this study, we examined if the reduction of Cnbp affects the Central Nervous System (CNS). MRI and DTI analyses showed that total brain volume and grey matter are reduced in Cnbp KO mice, while mean, radial and axonal brain diffusivity is increased. The morphological changes in the brains of Cnbp KO mice are accompanied by reduced stereotypic behavior, anxiety and neuromotor defects. These findings suggest that the reduction of CNBP contributes to CNS pathology in DM2. Since CNBP stability is regulated by pAMPK-dependent phosphorylation, we examined protein levels of pAMPK in DM2 cells and found that the active pAMPK is reduced in DM2. Interaction of CNBP with pAMPK and stability of CNBP protein are also decreased in DM2. Our data show that a small molecule AMPK activator A769662 corrects CNBP stability and normalizes CNBP targets in DM2 fibroblasts. Thus, activators of AMPK could potentially be developed as therapeutics to correct CNBP and reduce muscle and brain atrophies in DM2.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"512-522"},"PeriodicalIF":3.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UBE2S, downregulated by miR-152-3p, facilitates prostate cancer progression through the PTEN-mediated AKT/mTOR pathway.","authors":"Chunhui Wang, Gang Zhang, Ying Jiang, Guochang Bao, Chunsheng Li","doi":"10.1093/hmg/ddaf004","DOIUrl":"10.1093/hmg/ddaf004","url":null,"abstract":"<p><strong>Objectives: </strong>In recent years, the incidence and mortality rates of prostate cancer (PCa) have still not been significantly reduced and the mechanisms of tumor onset and progression are still not fully understood. The pathogenic mechanisms and upstream regulation of UBE2S expression in prostate cancer have not been elucidated.</p><p><strong>Methods: </strong>Here, we performed bioinformatic analysis of public databases to reveal the expression of UBE2S in PCa and its association with Gleason score, tumor staging, biochemical recurrence, and survival. Subsequently, the effect of UBE2S on the proliferation and invasive capacity of PCa cells was explored. Next, miR-152-3p was identified to bind to the 3'-UTR of UBE2S mRNA and down-regulated in PCa through luciferase reporter assays. Dual immunofluorescence assay and co-immunoprecipitation assays were performed to verify the regulatory role of UBE2S on PTEN. Finally, the molecular mechanism of UBE2S regulation of PCa progression was further confirmed by rescue experiments and in vivo nude mouse subcutaneous transplantation tumor experiments.</p><p><strong>Results: </strong>UBE2S expression was upregulated in PCa and correlated with patient Gleason score, TNM stage, biochemical recurrence, and disease-free survival. miR-152-3p regulated UBE2S expression in PCa by binding to the UBE2S mRNA 3'-UTR. Mechanistically, UBE2S combines with PTEN and ubiquitinates it, leading to PTEN degradation and ultimately promoting PCa progression via the AKT/mTOR signaling pathway.</p><p><strong>Conclusions: </strong>UBE2S, down-regulated by miR-152-3p, plays an important role in the onset and progression of PCa through the PTEN-mediated Akt/mTOR pathway and may become a new diagnostic marker and therapeutic target for PCa.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"523-532"},"PeriodicalIF":3.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}