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Cohesin complexes with a potential to link mammalian meiosis to cancer

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Cell Regeneration 2013年第1期2卷 26-33页

作者： Alexander Strunnikov Guangzhou Institutes of Biomedicine and Health Molecular Epigenetics Laboratory190 Kai Yuan AvenueScience ParkGuangzhou 510530China

Among multiple genes aberrantly activated in cancers,invariably,there is a group related to the capacity of cell to *** of these genes are related to the normal process of development,including the establishment of a *** group,a part of growing family of cancer/Testis(CT)genes,now includes the meiosis specific subunits of cohesin *** first reports characterizing the SMC1 and RAD21 genes,encoding subunits of cohesin,were published 20 years ago;however the exact molecular mechanics of cohesin molecular machine in vivo remains rather obscure notwithstanding ample elegant *** matters are complicated by the fact that the evolution of cohesin function,which is served by just two basic types of protein complexes in budding yeast,took an explosive turn in *** recent characterization of a new set of genes encoding cohesin subunits specific for meiosis in vertebrates adds several levels of complexity to the task of structurefunction analysis of specific cohesin pathways,even more so in relation to their aberrant functionality in *** three proteins,SMC1β,RAD21L and STAG3 are likely involved in a specific function in the first meiotic prophase,genetic recombination,and segregation of ***,at present,it is rather challenging to pinpoint the molecular role of these proteins,particularly in synaptonemal complex or centromere function,due to the multiplicity of different cohesins in *** roles of these proteins in cancer cell physiology,upon their aberrant activation in tumors,also remain to be ***,as the existence of cancer/Testis cohesin complexes in tumor cells appears to be all but certain,this brings a promise of a new target for cancer therapy and/or diagnostics.

关键词： Spermatogenesis Germline Chromothripsis CTCFL BORIS CTCF SMC Kleisin

Hepatocellular carcinoma: Understanding molecular mechanisms for defining potential clinical modalities

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World Journal of Hepatology 2021年第11期13卷 1568-1583页

作者： Abhiram Natu Anjali Singh Sanjay Gupta epigenetics and Chromatin Biology Group Gupta LaboratoryCancer Research InstituteAdvanced Centre for TreatmentResearch and Education in CancerTata Memorial CentreKhargharNavi Mumbai 410210MaharashtraIndia Homi Bhabha National Institute Training School ComplexAnushakti NagarMumbai 400085MaharashtraIndia

Liver cancer is the sixth most commonly occurring cancer and costs millions of lives per *** diagnosis of hepatocellular carcinoma(HCC)has relied on scanning techniques and serum-based markers such asα-*** measures have limitations due to their detection limits and asymptomatic conditions during the early stages,resulting in late-stage cancer diagnosis where targeted chemotherapy or systemic treatment with sorafenib is ***,the aid of conventional therapy for patients in the advanced stage of HCC has limited ***,it is essential to seek a new treatment strategy and improve the diagnostic techniques to manage the *** have used the omics profile of HCC patients for sub-classification of tissues into different groups,which has helped us with *** these efforts,a promising target for treatment has not been *** hurdle in this situation is genetic and epigenetic variations in the tumor,leading to disparities in response to *** reversible epigenetic changes along with clinical traits help to define new markers for patient categorization and design personalized *** clinical trials of inhibitors of epigenetic modifiers(also known as epi-drugs)are in ***-drugs like azacytidine or belinostat are already approved for other cancer ***,epigenetic changes have also been observed in drug-resistant HCC *** such cases,combinatorial treatment of epi-drugs with systemic therapy or trans-arterial chemoembolization might re-sensitize resistant cells.

关键词： Hepatocellular carcinoma Diagnosis Treatment epigenetics Epi-drugs Drug resistance

Detection and surveillance of circulating tumor cells in osteosarcoma for predicting therapy response and prognosis

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cancer Biology & Medicine 2022年第9期19卷 1397-1409页

作者： Haoran Mu Dongqing Zuo Jie Chen Zhigang Liu Zhuo Wang Liu Yang Qihui Shi Yingqi Hua Shanghai Bone Tumor Institute and Department of Orthopedics Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghai 200080China Key laboratory of Systems Biomedicine(Ministry of Education) Shanghai Center for Systems BiomedicineShanghai Jiao Tong UniversityShanghai 200240China Shanghai Key laboratory of Medical epigenetics and the International Co-laboratory of Medical epigenetics and Metabolism(MOST) Institutes of Biomedical SciencesFudan UniversityShanghai 200032China Key laboratory of Whole-Period Monitoring and Precise Intervention of Digestive cancer(SMHC)and Institute of Fudan-Minhang Academic Health System Minhang HospitalFudan UniversityShanghai 201199China Shanghai Engineering Research Center of Biomedical Analysis Reagents Shanghai 201203China

Objective:Osteosarcoma(OS)is an aggressive,highly metastatic,relatively drug-resistant bone tumor with poor long-term survival *** presence and persistence of circulating tumor cells(CTCs)in the peripheral blood are believed to be associated with treatment inefficiency and distant metastases.A blood-based CTC test is thus greatly needed for monitoring disease progression and predicting clinical ***,traditional methods cannot detect CTCs from tumors of mesenchymal origin such as OS,and research on CTC detection in mesenchymal tumors has been hindered for ***:In this study,we developed a CTC test based on hexokinase 2,a metabolic function-associated marker,for the detection and surveillance of OS CTCs,and subsequently explored its clinical *** patients with OS were enrolled as the training cohort for serial CTC *** CTC counting,in combination with therapy evaluation and post-treatment follow-up,was used to establish a model for predicting post-chemotherapy evaluation and disease-free survival,and the model was further validated with a cohort of 8 patients with ***:Two dynamic CTC number patterns were identified,and the resulting predictive model exhibited 92%consistency with the clinical *** model suggested that a single CTC test has similar predictive power to serial CTC *** the validation cohort,the single CTC test exhibited 100%and 87.5%consistency with therapy response and disease-free survival,***:Our non-invasive test for detection and surveillance of CTCs enables accurate prediction of therapy efficiency and prognosis,and may be clinically valuable for avoiding inefficient therapy and prolonging survival.

关键词： Circulating tumor cells osteosarcoma hexokinase 2 single-cell sequencing mesenchymal tumor

Cryo-shocked cancer cell microgels for tumor postoperative combination immunotherapy and tissue regeneration

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Bioactive Materials 2023年第10期28卷 326-336页

作者： Gaizhen Kuang Qingfei Zhang Yunru Yu Luoran Shang Yuanjin Zhao Department of Rheumatology and Immunology Nanjing Drum Tower HospitalSchool of Biological Science and Medical EngineeringSoutheast UniversityNanjing210096China Shanghai Xuhui Central Hospital Zhongshan-Xuhui Hospitaland the Shanghai Key Laboratory of Medical EpigeneticsThe International Co-laboratory of Medical Epigenetics and Metabolism(Ministry of Science and Technology)Institutes of Biomedical SciencesFudan UniversityShanghai200032China Oujiang laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325001China

Prevention of recurrence/metastasis and tissue regeneration are critical for post-surgery treatment of malignant tumors. Here, to address these needs, a novel type of microgel co-loading cryo-shocked cancer cells, immunoadjuvant, and immune checkpoint inhibitor is presented by microfluidic electrospray technology and liquid nitrogen treatment. Owing to the encapsulation of cryo-shocked cancer cells and immunoadjuvant, the microgels can recruit dendritic cells and activate them in situ, and evoke a robust immune response. Moreover, with the combination of the immune checkpoint inhibitor, the antitumor immune response is further enhanced by inhibiting the interaction of PD1 and PDL1. With this, the excellent anti-recurrence and anti-metastasis efficacy of the microgels are demonstrated in an orthotopic breast cancer mouse model. Besides, because of the excellent biocompatibility and appropriate degradation performance, the microgels can provide support for normal cell adhesion and growth, which is beneficial to tissue reconstruction. These properties indicate the great value of the cryo-shocked cancer cell microgels for efficient tumor postoperative combination immunotherapy and tissue regeneration.

关键词： Immunotherapy Microfluidics Microgel Vaccine Regeneration

Prostate cancer epigenetics and its clinicalmplications

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Asian Journal of Andrology 2016年第4期18卷 549-558页

作者： Srinivasan Yegnasubramanian Sidney Kimmel Comprehensive cancer Center Department of Oncology Johns Hopkins University School of Medicine Baltimore Maryland USA

Normal cells have a level of epigenetic programming that is superimposed on the genetic code to establish and maintain their cell identity and phenotypes. This epigenetic programming can be thought as the architecture, a sort of cityscape, that is built upon the underlying genetic landscape. The epigenetic programming is encoded by a complex set of chemical marks on DNA, on histone proteins in nucleosomes, and by numerous context-specific DNA, RNA, protein interactions that all regulate the structure, organization, and function of the genome in a given cell. It is becoming increasingly evident that abnormalities in both the genetic landscape and epigenetic cityscape can cooperate to drive carcinogenesis and disease progression. Large-scale cancer genome sequencing studies have revealed that mutations in genes encoding the enzymatic machinery for shaping the epigenetic cityscape are among the most common mutations observed in human cancers, including prostate cancer. Interestingly, although the constellation of genetic mutations in a given cancer can be quite heterogeneous from person to person, there are numerous epigenetic alterations that appear to be highly recurrent, and nearly universal in a given cancer type, including in prostate cancer. The highly recurrent nature of these alterations can be exploited for development of biomarkers for cancer detection and risk stratification and as targets for therapeutic intervention. Here, we explore the basic principles of epigenetic processes in normal cells and prostate cancer cells and discuss the potential clinical implications with regards to prostate cancer biomarker development and therapy.

关键词： biomarkers DNA methylation epigenetics epigenomics prostatic neoplasms tumor

Aberrant expression of enzymes regulating m^6A mRNA methylation: implication in cancer

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cancer Biology & Medicine 2018年第4期15卷 323-334页

作者： Natalia Pinello Stephanie Sun Justin Jong-Leong Wong epigenetics and RNA Biology Program Centenary Institute The University of Sydney Sydney Medical School The University of Sydney

N^6-methyladenosine(m^6 A) is an essential RNA modification that regulates key cellular processes, including stem cell renewal,cellular differentiation, and response to DNA damage. Unsurprisingly, aberrant m^6 A methylation has been implicated in the development and maintenance of diverse human cancers. Altered m^6 A levels affect RNA processing, mRNA degradation, and translation of mRNAs into proteins, thereby disrupting gene expression regulation and promoting tumorigenesis. Recent studies have reported that the abnormal expression of m^6 A regulatory enzymes affects m^6 A abundance and consequently dysregulates the expression of tumor suppressor genes and oncogenes, including MYC, SOCS2, ADAM19, and PTEN. In this review, we discuss the specific roles of m^6 A missing space "writers", "erasers", and "readers" in normal physiology and how their altered expression promotes tumorigenesis. We also describe the potential of exploiting the aberrant expression of these enzymes for cancer diagnosis, prognosis, and the development of novel therapies.

关键词： RNA modification N^6-methyladenosine (m^6A) cancer tumor suppressor oncogene

Epigenome-wide development and validation of a prognostic methylation score in intrahepatic cholangiocarcinoma based on machine learning strategies

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Hepatobiliary Surgery and Nutrition 2023年第4期12卷 478-494,I0001-I0006页

作者： Xing Chen Liangqing Dong Lu Chen Yuan Wang Jinpeng Du Lijie Ma Xiaokai Yan Jiwei Huang Mingheng Liao Xiangzheng Chen Dongming Liu Jin Li Bo Zhang Wen Teng Kefei Yuan Deqiang Sun Qiang Gao Yong Zeng Department of Liver Surgery&Liver Transplantation Laboratory of Liver SurgeryState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina Department of Liver Surgery and Transplantation Liver Cancer InstituteZhongshan HospitalKey Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationFudan UniversityShanghaiChina Key laboratory of Medical epigenetics and Metabolism Institutes of Biomedical SciencesFudan UniversityShanghaiChina Department of Hepatobiliary cancer Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin’s Clinical Research Center for CancerTianjinChina The Fifth Affiliated Hospital State Key Laboratory of Respiratory DiseaseGuangzhou Medical UniversityGuangzhouChina Department of Research and Development Jiangsu Gaomei GenomicsNanjingChina Department of Oncology the Second Affiliated Hospital of Zunyi Medical UniversityZunyiChina Department of Cardiology Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina

Background:Clinical parameter-based nomograms and staging systems provide limited information for the prediction of survival in intrahepatic cholangiocarcinoma(ICC)*** this study,we developed a methylation signature that precisely predicts overall survival(OS)after ***:An epigenome-wide study of DNA methylation based on whole-genome bisulfite sequencing(WGBS)was conducted for two independent cohorts(discovery cohort,n=164;validation cohort,n=170)from three hepatobiliary centers in *** referring to differentially methylated regions(DMRs),we proposed the concept of prognostically methylated regions(PMRs),which were composed of consecutive prognostically methylated CpGs(PMCs).Using machine learning strategies(Random Forest and the least absolute shrinkage and selector regression),a prognostic methylation score(PMS)was constructed based on 14 PMRs in the discovery cohort and confirmed in the validation ***:The C-indices of the PMS for predicting OS in the discovery and validation cohorts were 0.79 and 0.74,*** the whole cohort,the PMS was an independent predictor of OS[hazard ratio(HR)=8.12;95% confidence interval(CI):5.48-12.04;Pcancer(AJCC)tumor-node-metastasis(TNM)staging system(0.61,P<0.001),and MEGNA prognostic score(0.60,P<0.001).The patients in quartile 4 of PMS could benefit from adjuvant therapy(AT)(HR=0.54;95%CI:0.32-0.91;log-rank P=0.043),whereas those in the quartiles 1-3 could ***,other nomograms and staging system failed to do *** analyses of potential mechanisms showed that the PMS was associated with tumor biological behaviors,pathway activation,and immune ***:The PMS could improve the prognostic accuracy and identify

关键词： Intrahepatic cholangiocarcinoma(ICC) prognostic methylation score(PMS) machine learning overall survival(OS) adjuvant therapy(AT)

The Association Between H3K4me3 and Antisense Transcription

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Genomics, Proteomics & Bioinformatics 2012年第2期10卷 74-81页

作者： Peng Cui Wanfei Liu Yuhui Zhao Qiang Lin Feng Ding Chengqi Xin Jianing Geng Shuhui Song Fanglin Sun Songnian Hu Jun Yu CAS Key laboratory of Genome Sciences and Information Beijing Institute of GenomicsChinese Academy of SciencesBeijing 100029China Institute of epigenetics and cancer Research School of MedicineTsinghua UniversityBeijing 100080China Graduate University of Chinese Academy of Sciences Beijing 100049China

Histone H3 lysine 4 trimethylation （H3K4me3） is well known to occur in the promoter region of genes for transcription activation. How- ever, when investigating the H3K4me3 profiles in the mouse cerebrum and testis, we discovered that H3K4me3 also has a significant enrichment at the 3＇ end of actively transcribed （sense） genes, named as 3＇-H3K4me3. 3＇-H3K4me3 is associated with ~15% of pro- tein-coding genes in both tissues. In addition, we examined the transcriptional initiation signals including RNA polymerase II （RNAPII） binding sites and Y-CAGE-tag that marks transcriptional start sites. Interestingly, we found that 3＇-H3K4me3 is associated with the ini- tiation of antisense transcription. Furthermore, 3＇-H3K4me3 modification levels correlate positively with the antisense expression levels of the associated sense genes, implying that 3＇-H3K4me3 is involved in the activation of antisense transcription. Taken together, our findings suggest that H3K4me3 may be involved in the regulation of antisense transcription that initiates from the 3＇ end of sense genes. In addition, a positive correlation was also observed between the expression of antisense and the associated sense genes with 3＇-H3K4me3 modification. More importantly, we observed the 3＇-H3K4me3 enrichment among genes in human, fruitfly and Arabidopsis, and found that the sequences of 3＇-H3K4me3-marked regions are highly conserved and essentially indistinguishable from known promoters in ver- tebrate. Therefore, we speculate that these 3＇-H3K4me3-marked regions may serve as potential promoters for antisense transcription and 3＇-H3K4me3 appear to be a universal epigenetic feature in eukaryotes. Our results provide a novel insight into the epigenetic roles of H3K4me3 and the regulatory mechanism of antisense transcription.

关键词： Antisense initiation and activation Antisense transcription H3K4me3

Jumonji domain-containing protein family： the functions beyond lysine demethylation

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Journal of Molecular Cell Biology 2018年第4期10卷 371-373页

作者： Yuan Meng Hongzhi Li Changwei Liu Li Zheng Binghui Shen Department of cancer Genetics and epigenetics Beckman Research Institute of City of Hope Duarte CA 91010 USA Department of Molecular Medicine Beckman Research Institute of City of Hope Duarte CA 91010 USA

Two of the unsolved but important questions in epigenetics are whether arginine demethylases （RDMs） exist and whether proteolytic cleavage of the histone tails and subsequent histone remodeling are a major epigenetic modification process. Jumonji domain （JmjC）-containing proteins have been characterized as lysine demethylases （KDMs） in a certain degree （Klose et al., 2006）. Emerging evidences indicate that they also catalyze demethylation reaction on the arginine residues and proteolytic removal of histone tails. These processes are likely associated with biological meanings.

关键词：精氨酸蛋白质包含域家庭尾巴生物