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Interruption of Klf5 acetylation in basal progenitor cells promotes luminal commitment by activating Notch signaling

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Journal of Genetics and Genomics 2022年第6期49卷 579-582页

作者： Baotong Zhang Siyuan Xia Mingcheng Liu Xiawei Li Shimin Shuai Wei Tao Yixiang Li Jianping Jenny Ni Wei Zhou Lan Liao Jianming Xu Jin-Tang Dong Department of Human Cell Biology and Genetics Southern University of Science and Technology School of MedicineShenzhenGuangdong 518055China Department of Hematology and Medical Oncology Emory University School of MedicineAtlantaGA 30322USA winship cancer institute Emory UniversityAtlantaGA 30322USA Department of Human Cell Biology and Genetics Southern University of Science and 7.Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonTXUSA

Prostate homeostasis and regeneration rely on the proper function of adult stem/progenitor cells(Ousset et al., 2012), which have also been considered as potential cells of origin for prostate cancer(Visvader, 2011) given their key positions in the lineage hierarchy and self-renewal capability. Accumulating evidence reveals the existence of multipotent progenitor cells in both basal and luminal cells.

关键词： progenitor luminal

A multiplexed time-resolved fluorescence resonance energy transfer ultrahigh-throughput screening assay for targeting the SMAD4–SMAD3–DNA complex

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Journal of Molecular Cell Biology 2023年第11期15卷 21-32页

作者： Wukun Ouyang Qianjin Li Qiankun Niu Min Qui Haian Fu Yuhong Du Xiulei Mo Department of Pharmacology and Chemical Biology Emory University School of MedicineAtlantaGA 30322USA Emory Chemical Biology Discovery Center Emory University School of MedicineAtlantaGA 30322USA Department of Hematology and Medical Oncology and winship cancer institute Emory UniversityAtlantaGA 30322USA

The transforming growth factor-beta(TGFβ)signaling pathway plays crucial roles in the establishment of an immunosuppressive tumor microenvironment,making anti-TGFβagents a significant area of interest in cancer ***,the clinical translation of current anti-TGFβagents that target upstream cytokines and receptors remains ***,the development of small-molecule inhibitors specifically targeting SMAD4,the downstream master regulator of the TGFβpathway,would offer an alternative approach with significant therapeutic potential for anti-TGFβ*** this study,we present the development of a cell lysate-based multiplexed time-resolved fluorescence resonance energy transfer(TR-FRET)assay in an ultrahigh-throughput screening(uHTS)1536-well plate *** assay enables simultaneous monitoring of the protein–protein interaction between SMAD4 and SMAD3,as well as the protein–DNA interaction between SMADs and their consensus DNA-binding *** multiplexed TR-FRET assay exhibits high sensitivity,allowing the dynamic analysis of the SMAD4–SMAD3–DNA complex at single-amino acid ***,the multiplexed uHTS assay demonstrates robustness for screening small-molecule *** a pilot screening of an FDA-approved bioactive compound library,we identified gambogic acid and gambogenic acid as potential hit *** proof-of-concept findings underscore the utility of our optimized multiplexed TR-FRET platform for large-scale screening to discover small-molecule inhibitors that target the SMAD4–SMAD3–DNA complex as novel antiTGFβsignaling agents.

关键词： TGFβ/SMAD4 signaling high-throughput screening TR-FRET

Atrial fibrillation in the elderly: the potential contribution of reactive oxygen species

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Journal of Geriatric Cardiology 2012年第4期9卷 379-388页

作者： Kurt J. Schillinger Vickas V. Patel Penn Cardiovascular institute and Section of Cardiac Electrophysiology University of Pennsylvania Philadelphia PA 19104 USA

Atrial fibrillation (AF) is the most commonly encountered cardiac arrhythmia, and is a significant source of healthcare expenditures throughout the world. It is an arrhythmia with a very clearly defined predisposition for individuals of advanced age, and this fact has led to intense study of the mechanistic links between aging and AF. By promoting oxidative damage tomultiple subcellular and cellular structures, reactive oxygen species (ROS) have been shown to induce the intra- and extra-cellular changes necessary to promote the pathogenesis of *** addition, the generation and accumulation of ROS have been intimately linked to the cellular processeswhich underlie aging. This review begins with an overview of AF pathophysiology, and introduces the critical structures which, when damaged, predispose an otherwise healthy atrium toAF. The available evidence thatROS can lead to damage of these critical structures is then reviewed. Finally, the evidence linking the process of aging to the pathogenesis of AF is discussed.

关键词： Aging Arrhythmia Atrial fibrillation Cardiac Free radicals Oxidative stress Redox

HER3-targeted therapeutic antibodies and antibody-drug conjugates in non-small cell lung cancer refractory to EGFR-tyrosine kinase inhibitors

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Chinese Medical Journal Pulmonary and Critical Care Medicine 2023年第1期1卷 11-17页

作者： Margaret E.Larsen Hui Lyu Bolin Liu Departments of Interdisciplinary Oncology and Genetics Stanley S.Scott Cancer CenterSchool of MedicineLouisiana State University(LSU)Health Sciences CenterNew OrleansLA 70112USA

Human epidermal growth factor receptor 3(HER3)is a unique member of the human epidermal growth factor receptor(HER/EGFR)family,since it has negligible kinase ***,HER3 must interact with a kinase-proficient receptor to form a heterodimer,leading to the activation of signaling *** of HER3 is observed in various human cancers,including non-small cell lung cancer(NSCLC),and correlates with poor clinical outcomes in *** on the underlying mechanism demonstrate that HER3-initiated signaling promotes tumor metastasis and causes treatment failure in human *** of HER3 is frequently observed in EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors(TKIs).Increased expression of HER3 triggers the so-called EGFR-independent mechanism via interactions with other receptors to activate“by-pass signaling pathways”,thereby resulting in resistance to *** date,no HER3-targeted therapy has been approved for cancer *** both preclinical and clinical studies,targeting HER3 with a blocking an-tibody(Ab)is the only strategy being *** evaluations of an anti-HER3 Ab-drug conjugate(ADC)show promising results in patients with EGFR-TKI-resistant ***,we summarize our understanding of the unique biology of HER3 in NSCLC refractory to EGFR-TKIs,with a focus on its dimerization partners and subsequent activation of signaling *** also discuss the latest development of the therapeutic Abs and ADCs targeting HER3 to abrogate EGFR-TKI resistance in NSCLC.

关键词： Human epidermal growth factor receptor 3(HER3) Epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKI) Resistance Antibody Antibody-drug conjugate(ADC) Non-small cell lung cancer(NSCLC)

Taking early preventive interventions to manage the challenging issue of acquired resistance to third-generation EGFR inhibitors

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Chinese Medical Journal Pulmonary and Critical Care Medicine 2023年第1期1卷 3-10页

作者： Shi-Yong Sun Department of Hematology and Medical Oncology Emory University School of Medicine and Winship Cancer Institute of Emory UniversityAtlantaGA 30322USA

Although the clinical efficacies of third-generation epidermal growth factor receptor(EGFR)-tyrosine kinase in-hibitors(TKIs)such as osimertinib in the treatment of non-small cell lung cancer(NSCLC)with EGFR-activating mutations are promising,drug-acquired resistance inevitably occurs whether they are used as first-line or second-line ***,managing the acquired resistance to third-generation EGFR-TKIs is crucial in the clinic for improving patient *** efforts have been made to develop potentially effective strategies or regimens for the treatment of EGFR-mutant NSCLC patients after relapse following these TKIs therapies with the hope that patients will continue to benefit from treatment through overcoming acquired *** this approach,which aims to overcome drug-acquired resistance,is necessary and important,it is a passive *** pre-ventive action early before disease progression to manage the unavoidable development of acquired resistance offers an equally important and efficient *** strongly believe that early preventive interventions using effective and tolerable combination regimens that interfere with the process of developing acquired resistance may substantially improve the outcomes of EGFR-mutant NSCLC treatment with third-generation ***,this review focuses on discussing the scientific rationale and mechanism-driven strategies for delaying and even preventing the emergence of acquired resistance to third-generation EGFR-TKIs,particularly osimertinib.

关键词： Lung cancer Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs) Osimertinib Acquired resistance EGFR mutations

Additive Effect of Zfhx3/Atbf1 and Pten Deletion on Mouse Prostatic Tumorigenesis

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Journal of Genetics and Genomics 2015年第7期42卷 373-382页

作者： Xiaodong Sun Changsheng Xing Xiaoying Fu Jie Li Baotong Zhang Henry F.Frierson Jr. Jin-Tang Dong winship cancer institute Department of Hematology and Medical OncologyEmory University School of Medicine Department of Pathology Tianjin University of Traditional Chinese Medicine Department of Pathology University of Virginia Health System

The phosphatase and tensin homolog （PTEN） and the zinc finger homeobox 3 （ZFHX3）/AT-motif binding factor 1 （ATBF1） genes have been established as tumor suppressor genes in prostate cancer by their frequent deletions and mutations in human prostate cancer and by the formation of mouse prostatic intraepithelial neoplasia （mPIN） or tumor by their deletions in mouse prostates. However, whether ZFHX3/ATBF1 deletion together with PTEN deletion facilitates prostatic tumorigenesis is unknown. In this study, we simultaneously deleted both genes in mouse prostatic epithelia and performed histological and molecular analyses. While deletion of one Pten allele alone caused low-grade （LG） mPIN as previously reported, concurrent deletion of Zfhx3/Atbfl promoted the progression to high-grade （HG） mPIN or early carcinoma. ZJhx3/Atbfl and Pten deletions together increased cell proliferation, disrupted the smooth muscle layer between epithelium and stroma, and increased the number of apoptotic cells. Deletion of both genes also accelerated the activation of Akt and Erkl/2 oncoproteins. These results suggest an additive effect of ZFHX3/ATBF1 and PTEN deletions on the development and progression of prostate neoplasia.

关键词： ZFHX3 ATBFI PTEN Prostate cancer mPIN

NSD3S stabilizes MYC through hindering its interaction with FBXW7

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Journal of Molecular Cell Biology 2020年第6期12卷 438-447页

作者： Valentina Gonzalez-Pecchi Albert KKwan Sean Doyle Andrey AIvanov Yuhong Du Haian Fu Graduate Program in cancer Biology Emory UniversityAtlantaGAUSA Department of Pharmacology and Chemical Biology Emory Chemical Biology Discovery CenterEmory UniversityAtlantaGAUSA winship cancer institute Emory UniversityAtlantaGAUSA Department of Hematology&Medical Oncology Emory UniversityAtlantaGAUSA

The MYC transcription factor plays a key role in cell growth control. Enhanced MYC protein stability has been found to promote tumorigenesis. Thus, understanding how MYC stability is controlled may have significant implications for revealing MYC-driven growth regulatory mechanisms in physiological and pathological processes. Our previous work identified the histone lysine methyltransferase nuclear receptor binding SET domain protein 3 (NSD3) as a MYC modulator. NSD3S, a noncatalytic isoform of NSD3 with oncogenic activity, appears to bind, stabilize, and activate the transcriptional activity of MYC. However, the mechanism by which NSD3S stabilizes MYC remains to be elucidated. To uncover the nature of the interaction and the underlying mechanism of MYC regulation by NSD3S, we characterized the binding interface between both proteins by narrowing the interface to a 15-amino acid region in NSD3S that is partially required for MYC regulation. Mechanistically, NSD3S binds to MYC and reduces the association of F-box and WD repeat domain containing 7 (FBXW7) with MYC, which results in suppression of FBXW7-mediated proteasomal degradation of MYC and an increase in MYC protein half-life. These results support a critical role for NSD3S in the regulation of MYC function and provide a novel mechanism for NSD3S oncogenic function through inhibition of FBXW7-mediated degradation of MYC.

关键词： cancer FBXW7 MYC NSD3S protein–protein interaction

Major histocompatibility complex I upregulation in clear cell renal cell carcinoma is associated with increased survival

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Asian Journal of Urology 2016年第2期3卷 75-81页

作者： Rishi R.Sekar Claire M.De La Calle Dattatraya Patil Sarah A.Holzman Yoram Baum Umer Sheikh Jonathan H.Huang Adeboye O.Osunkoya Brian P.Pollack Haydn T.Kissick Kenneth Ogan Viraj A.Master Department of Urology Emory University School of MedicineAtlantaGAUSA Department of Pathology Emory University School of MedicineAtlantaGAUSA Department of Dermatology Emory University School of MedicineAtlantaGAUSA The Atlanta VA Medical Center DecaturGAUSA

Objective:To examine the prognostic value of tumor major histocompatibility complex I(MHCI)expression on survival and recurrence in patients with clear cell renal cell carcinoma(RCC).Methods:Fifty-three patients that underwent nephrectomy at our institution for clear cell RCC(T1eT3)with4 years of follow-up were queried from our nephrectomy *** staining for MHCI was performed on tumor specimens and MHCI expression was quantified with an automated image analysis *** were divided into high and low MHCI expression groups in order to study the relationship between MHCI expression and prognosis using the KaplaneMeier method and log-rank ***:Overall survival and recurrence free survival were increased in the high MHCI expression group compared to the low MHCI expression group(log-rank,p=0.036 and p=0.028,respectively).Patients alive at the end of the study had higher MHCI expression(mean positivity score 0.82)than those that died of disease(mean positivity score 0.76,t test,p=0.030).Patients that did not develop recurrence during the study period had higher MHCI expression(mean positivity score 0.83)than those that did develop recurrence(mean positivity score 0.78),but this difference was not significant(t test,p =0.079).

关键词： Renal cell carcinoma Prognosis MHCI Biomarker

LKB1 tumor suppressor: Therapeutic opportunities knock when LKB1 is inactivated

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Genes & Diseases 2014年第1期1卷 64-74页

作者： Wei Zhou Jun Zhang Adam I.Marcus Department of Hematology and Medical Oncology The Winship Cancer InstituteEmory University School of MedicineAtlantaGeorgia

LKB1 is commonly thought of as a tumor suppressor gene because its hereditary mutation is responsible for a cancer syndrome,and somatic inactivation of LKB1 is found in nonsmall cell lung cancer,melanoma,and cervical ***,unlike other tumor suppressors whose main function is to either suppress cell proliferation or promote cell death,one of the functions of LKB1-regulated AMPK signaling is to suppress cell proliferation in order to promote cell survival under energetic stress *** unique,pro-survival function of LKB1 has led to the discovery of reagents,such as phenformin,that specifically exploit the vulnerability of LKB1-null cells in their defect in sensing energetic *** targeted agents represent a novel treatment strategy because they induce cell killing when LKB1 is *** review article summarizes various vulnerabilities of LKB1-mutant cells that have been reported in the literature and discusses the potential of using existing or developing novel reagents to target cancer cells with defective LKB1.

关键词： Metabolic stress Targeted therapy Tumor Suppressor Tumor vulnerability