Cellular & Molecular Biology Letters最新文献

{"title":"Single-cell RNA sequencing identifies inherent abnormalities of adipose-derived stem cells from nonlesional sites of patients with localized scleroderma.","authors":"Xuanyu Liu, Zhujun Li, Hayson Chenyu Wang, Meng Yuan, Jie Chen, Jiuzuo Huang, Nanze Yu, Zhou Zhou, Xiao Long","doi":"10.1186/s11658-024-00635-0","DOIUrl":"https://doi.org/10.1186/s11658-024-00635-0","url":null,"abstract":"<p><strong>Background: </strong>Localized scleroderma (LoS) is an autoimmune disorder that primarily affects the skin, and is often treated with autologous fat grafting (AFG). Nevertheless, the retention rate of AFG in patients with LoS is typically low. We hypothesize that the low retention rate may be partially attributed to the inherent abnormalities of adipose-derived stem cells (ASCs) from nonlesional sites of patients with LoS.</p><p><strong>Methods: </strong>We performed a comparative analysis of the single-cell transcriptome of the SVF from nonlesional sites of patients with LoS and healthy donors, including cellular compositional analysis, differential expression analysis, and high-dimensional weighted gene coexpression network analysis. Experimental validation with fluorescence-activated cell sorting and bleomycin-induced skin fibrosis mice models were conducted.</p><p><strong>Results: </strong>We found a significant reduction in the relative proportion of CD55^high interstitial progenitors in ASCs under the condition of LoS. Differential expression analysis revealed inherent abnormalities of ASCs from patients with LoS, including enhanced fibrogenesis, reduced anti-inflammatory properties, and increased oxidative stress. Compared with CD55^low ASCs, CD55^high ASCs expressed significantly higher levels of secreted protein genes that had functions related to anti-inflammation and tissue regeneration (such as CD55, MFAP5, and METRNL). Meanwhile, CD55^high ASCs expressed significantly lower levels of secreted protein genes that promote inflammation, such as chemokine and complement protein genes. Furthermore, we provided in vivo experimental evidence that CD55^high ASCs had superior treatment efficacy compared with CD55^low ASCs in bleomycin-induced skin fibrosis mice models.</p><p><strong>Conclusions: </strong>We found that the low retention rate of AFG may be partially ascribed to the reduced pool of interstitial progenitor cells (CD55^high) present within the ASC population in patients with LoS. We demonstrated the potential for improving the efficacy of AFG in the treatment of LoS by restoring the pool of interstitial progenitors within ASCs. Our study has significant implications for the field of translational regenerative medicine.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pterostilbene improves neurological dysfunction and neuroinflammation after ischaemic stroke via HDAC3/Nrf1-mediated microglial activation.","authors":"Yuhua Chen, Wei He, Junlin Qiu, Yangyang Luo, Chenlong Jiang, Feng Zhao, Hong Wei, Jiao Meng, Tianlin Long, Xin Zhang, Lingjian Yang, Quanhua Xu, Juning Wang, Chi Zhang","doi":"10.1186/s11658-024-00634-1","DOIUrl":"10.1186/s11658-024-00634-1","url":null,"abstract":"<p><strong>Background: </strong>Stroke is a type of acute brain damage that can lead to a series of serious public health challenges. Demonstrating the molecular mechanism of stroke-related neural cell degeneration could help identify a more efficient treatment for stroke patients. Further elucidation of factors that regulate microglia and nuclear factor (erythroid-derived 2)-like 1 (Nrf1) may lead to a promising strategy for treating neuroinflammation after ischaemic stroke. In this study, we investigated the possible role of pterostilbene (PTS) in Nrf1 regulation in cell and animal models of ischaemia stroke.</p><p><strong>Methods: </strong>We administered PTS, ITSA1 (an HDAC activator) and RGFP966 (a selective HDAC3 inhibitor) in a mouse model of middle cerebral artery occlusion-reperfusion (MCAO/R) and a model of microglial oxygen‒glucose deprivation/reperfusion (OGD/R). The brain infarct size, neuroinflammation and microglial availability were also determined. Dual-luciferase reporter, Nrf1 protein stability and co-immunoprecipitation assays were conducted to analyse histone deacetylase 3 (HDAC3)/Nrf1-regulated Nrf1 in an OGD/R-induced microglial injury model.</p><p><strong>Results: </strong>We found that PTS decreased HDAC3 expression and activity, increased Nrf1 acetylation in the cell nucleus and inhibited the interaction of Nrf1 with p65 and p65 accumulation, which reduced infarct volume and neuroinflammation (iNOS/Arg1, TNF-α and IL-1β levels) after ischaemic stroke. Furthermore, the CSF1R inhibitor PLX5622 induced elimination of microglia and attenuated the therapeutic effect of PTS following MCAO/R. In the OGD/R model, PTS relieved OGD/R-induced microglial injury and TNF-α and IL-1β release, which were dependent on Nrf1 acetylation through the upregulation of HDAC3/Nrf1 signalling in microglia. However, the K105R or/and K139R mutants of Nrf1 counteracted the impact of PTS in the OGD/R-induced microglial injury model, which indicates that PTS treatment might be a promising strategy for ischaemia stroke therapy.</p><p><strong>Conclusion: </strong>The HDAC3/Nrf1 pathway regulates the stability and function of Nrf1 in microglial activation and neuroinflammation, which may depend on the acetylation of the lysine 105 and 139 residues in Nrf1. This mechanism was first identified as a potential regulatory mechanism of PTS-based neuroprotection in our research, which may provide new insight into further translational applications of natural products such as PTS.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11360871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triptolide-induced cuproptosis is a novel antitumor strategy for the treatment of cervical cancer.","authors":"Yanxia Xiao, Jiameng Yin, Pu Liu, Xin Zhang, Yajun Lin, Jun Guo","doi":"10.1186/s11658-024-00623-4","DOIUrl":"https://doi.org/10.1186/s11658-024-00623-4","url":null,"abstract":"<p><strong>Background: </strong>Cuproptosis is a unique copper-dependent form of cell death that is highly correlated with the metabolic state of cells. Triptolide exerts pharmacological activity by altering the regulation of metal ions. Cuproptosis is poorly understood in cancer, so in this study, we explored whether triptolide could induce cuproptosis in cervical cancer cells.</p><p><strong>Methods: </strong>The human cervical cancer cell lines HeLa and SiHa, which primarily rely on oxidative phosphorylation, were treated with triptolide. Cell viability, proliferation and migration, copper levels and cuproptosis-related protein levels were evaluated in these cell lines. The copper ion chelator tetrathiomolybdate (TTM) was administered to determine whether it could reverse the cuproptosis induced by triptolide. In addition, a nude mouse cervical cancer xenograft model was established to determine the effects of triptolide on cuproptosis in isolated tumor tissues.</p><p><strong>Results: </strong>The copper concentration increased with triptolide treatment. The levels of cuproptosis -related proteins, such as FDX1, LIAS, and DLAT, in the HeLa and SiHa cell lines decreased with triptolide treatment. XIAP, the target of triptolide, played a role in cuproptosis by regulating COMMD1. The level of copper exporters (ATP7A/B) decreased, but the level of the copper importer (CTR1) did not change with triptolide treatment. Furthermore, triptolide inhibited cervical cancer growth and induced cuproptosis in vivo.</p><p><strong>Conclusions: </strong>In summary, we report a new antitumor mechanism by which triptolide disrupted intracellular copper homeostasis and induced cuproptosis in cervical cancer by regulating the XIAP/COMMD1/ATP7A/B axis.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11360305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CLDN6 inhibits breast cancer growth and metastasis through SREBP1-mediated RAS palmitoylation.","authors":"Qiu Jin, Da Qi, Mingzi Zhang, Huinan Qu, Yuan Dong, Minghao Sun, Chengshi Quan","doi":"10.1186/s11658-024-00629-y","DOIUrl":"10.1186/s11658-024-00629-y","url":null,"abstract":"<p><strong>Background: </strong>Breast cancer (BC) ranks as the third most fatal malignant tumor worldwide, with a strong reliance on fatty acid metabolism. CLDN6, a candidate BC suppressor gene, was previously identified as a regulator of fatty acid biosynthesis; however, the underlying mechanism remains elusive. In this research, we aim to clarify the specific mechanism through which CLDN6 modulates fatty acid anabolism and its impact on BC growth and metastasis.</p><p><strong>Methods: </strong>Cell function assays, tumor xenograft mouse models, and lung metastasis mouse models were conducted to evaluate BC growth and metastasis. Human palmitic acid assay, triglyceride assay, Nile red staining, and oil red O staining were employed to investigate fatty acid anabolism. Reverse transcription polymerase chain reaction (RT-PCR), western blot, immunohistochemistry (IHC) assay, nuclear fractionation, immunofluorescence (IF), immunoprecipitation and acyl-biotin exchange (IP-ABE), chromatin immunoprecipitation (ChIP), dual luciferase reporter assay, and co-immunoprecipitation (Co-IP) were applied to elucidate the underlying molecular mechanism. Moreover, tissue microarrays of BC were analyzed to explore the clinical implications.</p><p><strong>Results: </strong>We identified that CLDN6 inhibited BC growth and metastasis by impeding RAS palmitoylation both in vitro and in vivo. We proposed a unique theory suggesting that CLDN6 suppressed RAS palmitoylation through SREBP1-modulated de novo palmitic acid synthesis. Mechanistically, CLDN6 interacted with MAGI2 to prevent KLF5 from entering the nucleus, thereby restraining SREBF1 transcription. The downregulation of SREBP1 reduced de novo palmitic acid synthesis, hindering RAS palmitoylation and subsequent endosomal sorting complex required for transport (ESCRT)-mediated plasma membrane localization required for RAS oncogenic activation. Besides, targeting inhibition of RAS palmitoylation synergized with CLDN6 to repress BC progression.</p><p><strong>Conclusions: </strong>Our findings provide compelling evidence that CLDN6 suppresses the palmitic acid-induced RAS palmitoylation through the MAGI2/KLF5/SREBP1 axis, thereby impeding BC malignant progression. These results propose a new insight that monitoring CLDN6 expression alongside targeting inhibition of palmitic acid-mediated palmitoylation could be a viable strategy for treating oncogenic RAS-driven BC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NXPH4 mediated by m⁵C contributes to the malignant characteristics of colorectal cancer via inhibiting HIF1A degradation.","authors":"Lei Yang, Jiawen Shi, Mingyang Zhong, Pingping Sun, Xiaojing Zhang, Zhengyi Lian, Hang Yin, Lijun Xu, Guyin He, Haiyan Xu, Han Wu, Ziheng Wang, Kai Miao, Jianfei Huang","doi":"10.1186/s11658-024-00630-5","DOIUrl":"10.1186/s11658-024-00630-5","url":null,"abstract":"<p><strong>Objective: </strong>Colorectal cancer (CRC) is a form of malignancy that exhibits a comparatively elevated occurrence and fatality rate. Given the relatively slower progress in diagnostic and therapeutic approaches for CRC, there is a need to investigate more accurate and efficient biomarkers.</p><p><strong>Methods: </strong>Core regulatory genes were screened using the TCGA database, and the expression of neurexophilin 4 (NXPH4) and its prognostic implications were validated using tissue microarray staining. The assessment of NXPH4 functions involved a range of experiments, including cellular, organoid, and murine models. Furthermore, a regulatory network between m⁵C, NXPH4, and HIF1A was established through several in vitro experiments.</p><p><strong>Results: </strong>The overexpression of NXPH4 is associated with unfavorable prognoses in patients with CRC and hepatocellular carcinoma. Additionally, it facilitates the progression of malignant tumors both in laboratory settings and in living organisms of colorectal carcinoma. Our research also reveals that NXPH4 mRNA can avoid degradation through RNautophagy, relying on an m⁵C-dependent mechanism. Moreover, NXPH4 amplifies the HIF signaling pathway and stabilizes HIF1A by competitively binding to PHD4.</p><p><strong>Conclusions: </strong>NXPH4, regulated by m⁵C, promotes malignant tumor progression and regulates the HIF pathway. Consequently, targeting NXPH4 through molecular therapies could potentially serve as an efficacious therapeutic strategy for the management of CRC exhibiting elevated NXPH4 expression.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PTBP1 knockdown impairs autophagy flux and inhibits gastric cancer progression through TXNIP-mediated oxidative stress.","authors":"Shimin Wang, Xiaolin Wang, Changhong Qin, Ce Liang, Wei Li, Ai Ran, Qiang Ma, Xiaojuan Pan, Feifei Yang, Junwu Ren, Bo Huang, Yuying Liu, Yuying Zhang, Haiping Li, Hao Ning, Yan Jiang, Bin Xiao","doi":"10.1186/s11658-024-00626-1","DOIUrl":"10.1186/s11658-024-00626-1","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) is a prevalent malignant tumor, and the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) has been identified as a crucial factor in various tumor types. Moreover, abnormal autophagy levels have been shown to significantly impact tumorigenesis and progression. Despite this, the precise regulatory mechanism of PTBP1 in autophagy regulation in GC remains poorly understood.</p><p><strong>Methods: </strong>To assess the expression of PTBP1 in GC, we employed a comprehensive approach utilizing western blot, real-time quantitative polymerase chain reaction (RT-qPCR), and bioinformatics analysis. To further identify the downstream target genes that bind to PTBP1 in GC cells, we utilized RNA immunoprecipitation coupled with sequencing (si-PTBP1 RNA-seq). To evaluate the impact of PTBP1 on gastric carcinogenesis, we conducted CCK-8 assays, colony formation assays, and GC xenograft mouse model assays. Additionally, we utilized a transmission electron microscope, immunofluorescence, flow cytometry, western blot, RT-qPCR, and GC xenograft mouse model experiments to elucidate the specific mechanism underlying PTBP1's regulation of autophagy in GC.</p><p><strong>Results: </strong>Our findings indicated that PTBP1 was significantly overexpressed in GC tissues compared with adjacent normal tissues. Silencing PTBP1 resulted in abnormal accumulation of autophagosomes, thereby inhibiting GC cell viability both in vitro and in vivo. Mechanistically, interference with PTBP1 promoted the stability of thioredoxin-interacting protein (TXNIP) mRNA, leading to increased TXNIP-mediated oxidative stress. Consequently, this impaired lysosomal function, ultimately resulting in blockage of autophagic flux. Furthermore, our results suggested that interference with PTBP1 enhanced the antitumor effects of chloroquine, both in vitro and in vivo.</p><p><strong>Conclusion: </strong>PTBP1 knockdown impairs GC progression by directly binding to TXNIP mRNA and promoting its expression. Based on these results, PTBP1 emerges as a promising therapeutic target for GC.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11330137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL3-mediated m⁶A modification of circGLIS3 promotes prostate cancer progression and represents a potential target for ARSI therapy.","authors":"Xiaofeng Cheng, Heng Yang, Yujun Chen, Zhenhao Zeng, Yifu Liu, Xiaochen Zhou, Cheng Zhang, An Xie, Gongxian Wang","doi":"10.1186/s11658-024-00628-z","DOIUrl":"10.1186/s11658-024-00628-z","url":null,"abstract":"<p><strong>Background: </strong>Circular RNAs (circRNAs) have been shown to be involved in tumorigenesis and progression. However, the role of circGLIS3 (hsa_circ_0002874) in prostate cancer (PCa) has yet not been reported.</p><p><strong>Methods: </strong>Candidate circRNA were determined through comprehensive analysis of public datasets, PCa cell lines, and tissues data. A series of cellular functional assays, including CCK-8, colony formation, wound healing, and transwell assays were performed. Subsequently, RNA sequencing, RNA immunoprecipitation, methylated RNA immunoprecipitation, microRNA pulldown, luciferase reporter assay, and western blot were used to explore the underlying molecular mechanisms. Moreover, the xenograft tumor mouse model was established to elucidate the function of circGLIS3.</p><p><strong>Results: </strong>CircGLIS3, derived from exon 2 of the parental GLIS3 gene, was identified as a novel oncogenic circRNA in PCa that was closely associated with the biochemical recurrence. Its expression levels were upregulated in PCa tissues and cell lines as well as enzalutamide high-resistant cells. The cellular functional assays revealed that circGLIS3 promoted PCa cell proliferation, migration, and invasion. METTL3-mediated N⁶-methyladenosine (m⁶A) modification maintained its upregulation by enhancing its stability. Mechanically, CircGLIS3 sponged miR-661 to upregulate MDM2, thus regulating the p53 signaling pathway to promote cell proliferation, migration, and invasion. Furthermore, in vitro and in vivo experiments, the knockdown of circGLIS3 improved the response of PCa cells to ARSI therapies such as enzalutamide.</p><p><strong>Conclusions: </strong>METTL3-mediated m⁶A modification of circGLIS3 regulates the p53 signaling pathway via the miR-661/MDM2 axis, thereby facilitating PCa progression. Meanwhile, this study unveils a promising potential target for ARSI therapy for PCa.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11325714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk between SUMOylation and other post-translational modifications in breast cancer.","authors":"Bajin Wei, Fan Yang, Luyang Yu, Cong Qiu","doi":"10.1186/s11658-024-00624-3","DOIUrl":"10.1186/s11658-024-00624-3","url":null,"abstract":"<p><p>Breast cancer represents the most prevalent tumor type and a foremost cause of mortality among women globally. The complex pathophysiological processes of breast cancer tumorigenesis and progression are regulated by protein post-translational modifications (PTMs), which are triggered by different carcinogenic factors and signaling pathways, with small ubiquitin-like modifier (SUMOylation) emerging as a particularly pivotal player in this context. Recent studies have demonstrated that SUMOylation does not act alone, but interacts with other PTMs, such as phosphorylation, ubiquitination, acetylation, and methylation, thereby leading to the regulation of various pathological activities in breast cancer. This review explores novel and existing mechanisms of crosstalk between SUMOylation and other PTMs. Typically, SUMOylation is regulated by phosphorylation to exert feedback control, while also modulates subsequent ubiquitination, acetylation, or methylation. The crosstalk pairs in promoting or inhibiting breast cancer are protein-specific and site-specific. In mechanism, alterations in amino acid side chain charges, protein conformations, or the occupation of specific sites at specific domains or sites underlie the complex crosstalk. In summary, this review centers on elucidating the crosstalk between SUMOylation and other PTMs in breast cancer oncogenesis and progression and discuss the molecular mechanisms contributing to these interactions, offering insights into their potential applications in facilitating novel treatments for breast cancer.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11316377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141911973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Palmitoylation of synaptic proteins: roles in functional regulation and pathogenesis of neurodegenerative diseases.","authors":"Jiaying Peng, Danchan Liang, Zhonghao Zhang","doi":"10.1186/s11658-024-00625-2","DOIUrl":"10.1186/s11658-024-00625-2","url":null,"abstract":"<p><p>Palmitoylation is a type of lipid modification that plays an important role in various aspects of neuronal function. Over the past few decades, several studies have shown that the palmitoylation of synaptic proteins is involved in neurotransmission and synaptic functions. Palmitoyl acyltransferases (PATs), which belong to the DHHC family, are major players in the regulation of palmitoylation. Dysregulated palmitoylation of synaptic proteins and mutated/dysregulated DHHC proteins are associated with several neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). In this review, we summarize the recent discoveries on the subcellular distribution of DHHC proteins and analyze their expression patterns in different brain cells. In particular, this review discusses how palmitoylation of synaptic proteins regulates synaptic vesicle exocytotic fusion and the localization, clustering, and transport of several postsynaptic receptors, as well as the role of palmitoylation of other proteins in regulating synaptic proteins. Additionally, some of the specific known associations of these factors with neurodegenerative disorders are explored, with a few suggestions for the development of therapeutic strategies. Finally, this review provides possible directions for future research to reveal detailed and specific mechanisms underlying the roles of synaptic protein palmitoylation.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11316366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141911974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N⁶-methyladenosine-modified SRPK1 promotes aerobic glycolysis of lung adenocarcinoma via PKM splicing.","authors":"Anqi Wang, Yuanyuan Zeng, Weijie Zhang, Jian Zhao, Lirong Gao, Jianjun Li, Jianjie Zhu, Zeyi Liu, Jian-An Huang","doi":"10.1186/s11658-024-00622-5","DOIUrl":"10.1186/s11658-024-00622-5","url":null,"abstract":"<p><strong>Background: </strong>The RNA N⁶-methyladenosine (m⁶A) modification has become an essential hotspot in epigenetic modulation. Serine-arginine protein kinase 1 (SRPK1) is associated with the pathogenesis of various cancers. However, the m⁶A modification of SRPK1 and its association with the mechanism of in lung adenocarcinoma (LUAD) remains unclear.</p><p><strong>Methods: </strong>Western blotting and polymerase chain reaction (PCR) analyses were carried out to identify gene and protein expression. m⁶A epitranscriptomic microarray was utilized to the assess m⁶A profile. Loss and gain-of-function assays were carried out elucidate the impact of METTL3 and SRPK1 on LUAD glycolysis and tumorigenesis. RNA immunoprecipitation (RIP), m⁶A RNA immunoprecipitation (MeRIP), and RNA stability tests were employed to elucidate the SRPK1's METTL3-mediated m⁶A modification mechanism in LUAD. Metabolic quantification and co-immunoprecipitation assays were applied to investigate the molecular mechanism by which SRPK1 mediates LUAD metabolism.</p><p><strong>Results: </strong>The epitranscriptomic microarray assay revealed that SRPK1 could be hypermethylated and upregulated in LUAD. The main transmethylase METTL3 was upregulated and induced the aberrant high m⁶A levels of SRPK1. Mechanistically, SRPK1's m⁶A sites were directly methylated by METTL3, which also stabilized SRPK1 in an IGF2BP2-dependent manner. Methylated SRPK1 subsequently promoted LUAD progression through enhancing glycolysis. Further metabolic quantification, co-immunoprecipitation and western blot assays revealed that SRPK1 interacts with hnRNPA1, an important modulator of PKM splicing, and thus facilitates glycolysis by upregulating PKM2 in LUAD. Nevertheless, METTL3 inhibitor STM2457 can reverse the above effects in vitro and in vivo by suppressing SRPK1 and glycolysis in LUAD.</p><p><strong>Conclusion: </strong>It was revealed that in LUAD, aberrantly expressed METTL3 upregulated SRPK1 levels via an m⁶A-IGF2BP2-dependent mechanism. METTL3-induced SRPK1 fostered LUAD cell proliferation by enhancing glycolysis, and the small-molecule inhibitor STM2457 of METTL3 could be an alternative novel therapeutic strategy for individuals with LUAD.</p>","PeriodicalId":9688,"journal":{"name":"Cellular & Molecular Biology Letters","volume":null,"pages":null},"PeriodicalIF":9.2,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}