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PDK1 promotes breast cancer progression by enhancing the stability and transcriptional activity of HIF-1α

Genes & diseases 2024年第4期11卷 353-367页

作者： Yu Wei Dian Zhang He Shi Husun Qian Hongling Chen Qian Zeng Fangfang Jin Yan Ye Zuli Ou Minkang Guo Bianqin Guo Tingmei Chen Key laboratory of Clinical laboratory Diagnostics(Ministry of Education) College of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Chongqing Key laboratory of Translational Research for Cancer Metastasis and individualized Treatment Chongqing University Cancer HospitalChongqing 400030China

Pyruvate dehydrogenase kinase 1(PDK1)phosphorylates the pyruvate dehydroge-nase complex,which inhibits its activity.Inhibiting pyruvate dehydrogenase complex inhibits the tricarboxylic acid cycle and the reprogramming of tumor cell metabolism to glycolysis,which plays an important role in tumor progression.This study aims to elucidate how PDK1 pro-motes breast cancer progression.We found that PDK1 was highly expressed in breast cancer tissues,and PDK1 knockdown reduced the proliferation,migration,and tumorigenicity of breast cancer cells and inhibited the HIF-1α(hypoxia-inducible factor 1a)pathway.Further investigation showed that PDK1 promoted the protein stability of HIF-1αby reducing the level of ubiquitination of HIF-1a.The HIF-1αprotein levels were dependent on PDK1 kinase activity.Furthermore,HIF-1a phosphorylation at serine 451 was detected in wild-type breast cancer cells but not in PDK1 knockout breast cancer cells.The phosphorylation of HIF-1αat Ser 451 stabilized its protein levels by inhibiting the interaction of HIF-1a with von Hippel-Lindau and prolyl hydroxylase domain.We also found that PDK1 enhanced HIF-1αtranscriptional ac-tivity.In summary,PDK1 enhances HIF-1αprotein stability by phosphorylating HIF-1a at Ser451 and promotes HIF-1αtranscriptional activity by enhancing the binding of HIF-1αto P300.PDK1 and HIF-1a form a positive feedback loop to promote breast cancer progression.

关键词： Breast cancer HIF-1α PDK1 Protein phosphorylation Transcriptional activity

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Maize gets an iron boost:Biofortification breakthrough holds promise to combat iron deficiency

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Journal of Integrative Plant Biology 2024年第4期66卷 635-637页

作者： Sunil Kumar Sahu State Key laboratory of Agricultural genomics Key Laboratory of GenomicsMinistry of AgricultureBGI ResearchShenzhen 518083China BGI Research Wuhan 430074China

Micronutrient deficiencies affect more than two billion people worldwide,resulting in poor health,developmental issues,and even death.Iron deficiency is one of the most prevalent micronutrient deficiencies worldwide a... 详细信息

关键词： population breakthrough holds

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Prognostic and clinical value of circPRKCI expression in diverse human cancers

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Chinese Medical Journal 2024年第2期137卷 152-161页

作者： Zhongyue Liu Xiaolei Ren Zhimin Yang Lin Mei Wenyi Li Chao Tu Zhihong Li Department of Orthopedics The Second Xiangya Hospital of Central South UniversityChangshaHunan 410011China Hunan Key laboratory of Tumor Models and individualized medicine The Second Xiangya Hospital of Central South UniversityChangshaHunan 410011China

Background:Highly expressed in various human cancers,circular RNA Protein Kinase C Iota(circPRKCI)has been reported to play an important role in cancer development and progression.Herein,we sought to reveal the prognostic and clinical value of circPRKCI expression in diverse human cancers.Methods:We searched the Pubmed,Web of Science,and the Cochrane Library databases from inception until May 16,2021.The relationship between circPRKCI expression and cancer patients’survival,including overall survival(OS)and disease-free survival(DFS),was assessed by pooled hazard ratios(HR)with corresponding 95%confidence interval(CI).The correlation between circPRKCI expression and clinical outcomes was evaluated using odds ratios(OR)with corresponding 95%CI.The data were analyzed by STATA software(version 12.0)or Review Manager(RevMan 5.3).Results:A total of 15 studies with 1109 patients were incorporated into our meta-analysis.The results demonstrated that high circPRKCI expression was significantly related to poor OS(HR=1.96,95%CI:1.61,2.39,P<0.001)when compared with low circPRKCI expression in diverse human cancers.However,elevated circPRKCI expression was not associated with DFS(HR=1.34,95%CI:0.93,1.95,P=0.121).Furthermore,the patient with a higher circPRKCI expression was prone to have a larger tumor size,advanced clinical stage,and lymph node metastasis,but it was not significantly correlated with age,gender,and distant metastasis.Conclusion:Elevated circPRKCI expression was correlated with worse OS and unfavorable clinical features,suggesting a novel prognostic and predictive role of circPRKCI in diverse human cancers.

关键词： CircPRKCI Cancer Prognosis Overall survival Meta-analysis Circular RNA Protein Kinase C Iota

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The role of proteasomes in tumorigenesis

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Genes & diseases 2024年第4期11卷 155-169页

作者： Xiangyi Zhou Ruqing Xu Yue Wu Li Zhou Tingxiu Xiang Department of Oncology The First Affliated Hospital of Chongqing Medical UniversityChongqing 400016China Chongqing Key laboratory of Translational Research for Cancer Metastasis and individualized Treatment Chongqing University Cancer HospitalChongqing 400030China

Protein homeostasis is the basis of normal life activities,and the proteasomefamily plays an extremely important function in this process.The proteasome 2os is a concentric circle structure with twoαrings and twoβrings overlapped.The proteasome 2os can perform both ATP-dependent and non-ATP-dependent ubiquitination proteasome degradation by binding to various subunits(such as 19S,11S,and 200 PA),which is performed by its active subunitβ1,β2,andβ5.The proteasome can degrade misfolded,excess proteins tomaintain homeostasis.At the same time,it can be utilized by tumors to degrade over-proliferate and unwanted proteins to support their growth.Proteasomes can affect the development of tumors from several aspects including tumor signaling pathways such as NF-kB and p53,cell cycle,immune regulation,and drug resistance.Proteasome-encoding genes have been found to be overexpressed in a variety of tumors,providing a potential novel target for cancer therapy.In addition,proteasome inhibitors such as bortezomib,carfilzomib,and ixazomib have been put into clinical application as the first-line treatment of multiple myeloma.More and more studies have shown that it also has different therapeutic effects in other tumors such as hepatocellular carcinoma,non-small cell lung cancer,glioblastoma,and neuroblastoma.However,proteasome inhibitors are not much effective due to their tolerance and singleness in other tumors.Therefore,further studies on their mechanisms of action and drug interactions are needed to investigate their therapeutic potential.

关键词： Bortezomib Cancer therapy Immunoproteasome Multiplemyeloma Proteasome 20S Proteasome inhibitor Thymoproteasom

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Cross-sectional network analysis of plasma proteins/metabolites correlated with pathogenesis and therapeutic response in acute promyelocytic leukemia

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Frontiers of medicine 2024年第2期18卷 327-343页

作者： Niu Qiao Yizhu Lyu Feng Liu Yuliang Zhang Xiaolin Ma Xiaojing Lin Junyu Wang Yinyin Xie Ruihong Zhang Jing Qiao Hongming Zhu Li Chen Hai Fang Tong Yin Zhu Chen Qiang Tian Saijuan Chen Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China Department of Hematology Second Hospital of Dalian Medical UniversityDalian116021China

The treatment of PML/RARA+acute promyelocytic leukemia(APL)with all-trans-retinoic acid and arsenic trioxide(ATRA/ATO)has been recognized as a model for translational medicine research.Though an altered microenvironment is a general cancer hallmark,how APL blasts shape their plasma composition is poorly understood.Here,we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters,proteomes,and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction therapy.Our study revealed the two prominent features of the APL plasma,suggesting a possible involvement of APL blasts in modulating plasma composition.One was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts,and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/RARA.Furthermore,results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage,which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular proteins.Overall,our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment.

关键词： acute promyelocytic leukemia plasma proteomics plasma metabolomics cross-sectional correlation network pathogenesis treatment

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Applications of genetic code expansion technology in eukaryotes

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Protein & Cell 2024年第5期15卷 331-363页

作者： Qiao-ru Guo Yu J.Cao State Key laboratory of Chemical Oncogenomic Guangdong Provincial Key Laboratory of Chemical GenomicsPeking University Shenzhen Graduate SchoolShenzhen 518055China Institute of Chemical Biology Shenzhen Bay LaboratoryShenzhen 518132China

Unnatural amino acids(UAAs)have gained significant attention in protein engineering and drug development owing to their ability to introduce new chemical functionalities to proteins.In eukaryotes,genetic code expansion(GCE)enables the incorporation of UAAs and facilitates posttranscriptional modification(PTM),which is not feasible in prokaryotic systems.GCE is also a powerful tool for cell or animal imaging,the monitoring of protein interactions in target cells,drug development,and switch regulation.Therefore,there is keen interest in utilizing GCE in eukaryotic systems.This review provides an overview of the application of GCE in eukaryotic systems and discusses current challenges that need to be addressed.

关键词： genetic code expansion unnatural amino acid eukaryotes basic research therapeutic applications

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Discovery of a potent and highly selective inhibitor of SIRT6 against pancreatic cancer metastasis in vivo

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1302-1316页

作者： Xinyuan Xu Qian Zhang Xufeng Wang Jing Jin Chengwei Wu Li Feng Xiuyan Yang Mingzhu Zhao Yingyi Chen Shaoyong Lu Zhen Zheng Xiaobing Lan Yi Wang Yan Zheng Xuefeng Lu Qiufen Zhang Jian Zhang State Key laboratory of Medical genomics National Research Center for Translational Medicine at ShanghaiRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Medicinal Chemistry and BioinformaticsCenter Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of General Surgery Huashan HospitalCancer Metastasis InstituteFudan UniversityShanghai 200040China Institute of Immunology and the CAS Key laboratory of Innate Immunity and Chronic disease School of Basic Medicine and Medical CenterUniversity of Science and Technology of ChinaHefei 230026China Department of Assisted Reproduction Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China College of Pharmacy Ningxia Medical UniversityYinchuan 750004China Department of Pancreatic Surgery Shanghai General HospitalShanghai Key Laboratory of Pancreatic DiseaseInstitute of Pancreatic DiseaseShanghai Jiao Tong University School of MedicineShanghai 200080China

Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer.However,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered.Here,we developed a noveSIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(50) value of 0.98±0.13μmol/L.Moreover,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3)at concentrations up to 100μmol/L.The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses.Importantly,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis.To our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer.It not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.

关键词： SIRT6 Inhibitor Allosteric Selectivity Cocrystal Pancreatic cancer metastasis

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Laparoscopic vs open surgery for gastric cancer: Assessing time, recovery, complications, and markers

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World Journal of Gastrointestinal Surgery 2024年第1期16卷 40-48页

作者： Yun-Yao Lu Yun-Xiao Li Meng He Ya-Li Wang Chongqing Key laboratory of Translational Research for Cancer Metastasis and individualized Treatment Chongqing University Cancer HospitalChongqing 400030China

BACKGROUND Gastric cancer(GC)is one of the most common cancers worldwide.Morbidity and mortality have increased in recent years,making it an urgent issue to address.La-paroscopic radical surgery(LRS)is a crucial method for treating patients with GC;However,its influence on tumor markers is still under investigation.The data of 194 patients treated at Chongqing University Cancer Hospital bet-ween January 2018 and January 2019 were retrospectively analyzed.Patients who underwent traditional open surgery and LRS were assigned to the control(n=90)and observation groups(n=104),respectively.Independent sample t-tests andχ2 tests were used to compare the two groups based on clinical efficacy,changes in tumor marker levels after treatment,clinical data,and the incidence of posto-perative complications.To investigate the association between tumor marker levels and clinical efficacy in patients with GC,three-year recurrence rates in the two groups were compared.RESULTS Patients in the observation group had a shorter duration of operation,less in-traoperative blood loss,an earlier postoperative eating time,and a shorter hospital stay than those in the control group(P0.05).After treatment,the overall response rate in the control group was significantly lower than that in the observation group(P=0.001).Furthermore,after treatment,the levels of carbohydrate antigen 19-9,cancer antigen 72-4,carcinoembryonic antigen,and cancer antigen 125 decreased significantly.The observation group also exhibited a significantly lower incidence rate of postoperative complications compared to the control group(P0.05).CONCLUSION LRS effectively treats early gastric cancer by reducing intraoperative bleeding,length of hospital stays,and postoperative complications.It also significantly lowers tumor marker levels,

关键词： Laparoscopic radical surgery Gastric cancer Serum tumor markers Prognosis Recurrence Intraoperative bleeding

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Improving error-correcting capability in DNA digital storage via soft-decision decoding

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National Science Review 2024年第2期11卷 135-144页

作者：丁璐璐伍世刚候志浩李阿伦许亚苹冯虎潘玮华阮珏 Shenzhen Branch Guangdong Laboratory of Lingnan Modern AgricultureGenome Analysis Laboratory of the Ministry of Agriculture and Rural AffairsAgricultural Genomics Institute at ShenzhenChinese Academy of Agricultural Sciences Guangdong Provincial Key laboratory of Plant Molecular Breeding State Key Laboratory for Conservation and Utilization of Subtropical Agro-BioresourcesSouth China Agricultural University

Error-correcting codes(ECCs) employed in the state-of-the-art DNA digital storage(DDS) systems suffer from a trade-off between error-correcting capability and the proportion of redundancy. To address this issue, in this study, we introduce soft-decision decoding approach into DDS by proposing a DNA-specific error prediction model and a series of novel strategies. We demonstrate the effectiveness of our approach through a proof-of-concept DDS system based on Reed-Solomon(RS) code, named as Derrick. Derrick shows significant improvement in error-correcting capability without involving additional redundancy in both in vitro and in silico experiments, using various sequencing technologies such as Illumina, Pac Bio and Oxford Nanopore Technology(ONT). Notably, in vitro experiments using ONT sequencing at a depth of 7× reveal that Derrick, compared with the traditional hard-decision decoding strategy, doubles the error-correcting capability of RS code, decreases the proportion of matrices with decoding-failure by 229-fold, and amplifies the potential maximum storage volume by impressive 32 388-fold. Also, Derrick surpasses ‘state-of-the-art' DDS systems by comprehensively considering the information density and the minimum sequencing depth required for complete information recovery. Crucially, the soft-decision decoding strategy and key steps of Derrick are generalizable to other ECCs' decoding algorithms.

关键词： DNA digital storage (DDS) error-correcting code (ECC) soft-decision decoding error-correcting capability storage volume

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Insufficient TRPM5 Mediates Lipotoxicity-induced Pancreaticβ-cell Dysfunction

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Current Medical Science 2024年第2期44卷 346-354页

作者： Kai-yuan WANG Shi-mei WU Zheng-jian YAO Yun-xia ZHU Xiao HAN Key laboratory of Human Functional genomics of Jiangsu Province Department of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjing 211166China

Objective:While the reduction of transient receptor potential channel subfamily M member 5(TRPM5)has been reported in islet cells from type 2 diabetic(T2D)mouse models,its role in lipotoxicity-induced pancreaticβ-cell dysfunction remains unclear.This study aims to study its role.Methods:Pancreas slices were prepared from mice subjected to a high-fat-diet(HFD)at different time points,and TRPM5 expression in the pancreaticβcells was examined using immunofluorescence staining.Glucose-stimulated insulin secretion(GSIS)defects caused by lipotoxicity were mimicked by saturated fatty acid palmitate(Palm).Primary mouse islets and mouse insulinoma MIN6 cells were treated with Palm,and the TRPM5 expression was detected using qRT-PCR and Western blotting.Palm-induced GSIS defects were measured following siRNA-based Trpm5 knockdown.The detrimental effects of Palm on primary mouse islets were also assessed after overexpressing Trpm5 via an adenovirus-derived Trpm5(Ad-Trpm5).Results:HFD feeding decreased the mRNA levels and protein expression of TRPM5 in mouse pancreatic islets.Palm reduced TRPM5 protein expression in a time-and dose-dependent manner in MIN6 cells.Palm also inhibited TRPM5 expression in primary mouse islets.Knockdown of Trpm5 inhibited insulin secretion upon high glucose stimulation but had little effect on insulin biosynthesis.Overexpression of Trpm5 reversed Palm-induced GSIS defects and the production of functional maturation molecules unique toβcells.Conclusion:Our findings suggest that lipotoxicity inhibits TRPM5 expression in pancreaticβcells both in vivo and in vitro and,in turn,drivesβ-cell dysfunction.

关键词： type 2 diabetes β-cell dysfunction lipotoxicity TRPM5

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