Article
Chemistry, Multidisciplinary
Jiahui He, Zhiya Fan, Yinping Tian, Weiwei Yang, Yichao Zhou, Qiang Zhu, Wanjun Zhang, Weijie Qin, Wen Yi
Summary: Light control of OGT activity in cells has been achieved by replacing a catalytically essential lysine residue with a genetically encoded photocaged lysine, providing a valuable chemical tool to control cellular O-GlcNAc with spatiotemporal precision and aiding in a better understanding of O-GlcNAc function.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Review
Oncology
Matthew P. Parker, Kenneth R. Peterson, Chad Slawson
Summary: O-linked beta-N-acetylglucosamine (O-GlcNAc) is a post-translational modification linking nutrient flux to gene transcription. Aberrant O-GlcNAcylation is associated with cancer development, progression, and alterations in gene expression. O-GlcNAc cycling by OGT and OGA regulates various aspects of gene expression, including RNA polymerase function and transcription factor activity.
Article
Chemistry, Multidisciplinary
Matjaz Weiss, Elena M. Loi, Masa Sterle, Cyril Balsollier, Tihomir Tomasic, Roland J. Pieters, Martina Gobec, Marko Anderluh
Summary: The study found that new inhibitors of OGT did not significantly improve its inhibitory effect, using the existing inhibitor F20 as the basis to design a new series of compounds. Although some elongated compounds showed stronger inhibitory effects, they still had disadvantages compared to F20.
FRONTIERS IN CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Sheng Yan, Bin Peng, Shifeng Kan, Guangcan Shao, Zhikai Xiahou, Xiangyan Tang, Yong-Xiang Chen, Meng-Qiu Dong, Xiao Liu, Xingzhi Xu, Jing Li
Summary: This article investigates the impact of O-GlcNAc transferase (OGT) on PLK1, and finds that OGT can modify PLK1 through O-GlcNAcylation. Further research reveals that the T291A and T291N mutations increase the stability of PLK1 and lead to chromosome segregation defects and uterine carcinoma. The findings suggest that OGT exerts its mitotic function partially through O-GlcNAcylation of PLK1, which may contribute to tumorigenesis by elevating O-GlcNAc levels.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Yogita Sharma, Shimona Ahlawat, Alka Ashish, Alka Rao
Summary: This study describes the shape-function relationship of SvGT (S/O-HexNActransferase) in the glycosylation process of bacteriocin SvC (ORF AQF52_3099) in Streptomyces venezuelae ATCC 15439. Experimental data confirmed that SvGT protein adopts an elongated dimeric shape in solution. The activation of SvGT requires the availability of Mg2+ ions, as confirmed by enzyme assays. SAXS analysis revealed the structural changes induced by Mg2+ ions and the role of conserved residues in the catalytic motif of SvGT.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Cell Biology
Ramkumar Mohan, Seokwon Jo, Elina Da Sol Chung, Eunice Oribamise, Amber Lockridge, Juan E. Abrahante-Llorens, Hai-Bin Ruan, Xiao-Yong Yang, Emilyn U. Alejandro
Summary: The study revealed that beta-cell Ogt overexpression in mice led to glucose intolerance under metabolic stressors such as high-fat diet and streptozocin, despite normal insulin secretion and beta-cell mass. Additionally, female mice with beta Ogt overexpression developed hyperglycemia and glucose intolerance post-treatment with streptozocin, contrary to the typical resistance seen in female mice. Transcriptional analysis showed common altered pathways involving pro-survival and inflammatory regulators in islets with loss or gain of Ogt. These findings suggest a gene dosage effect of Ogt and highlight the importance of O-GlcNAc cycling in beta-cell survival and function for glucose homeostasis.
Article
Oncology
Di Wang, Jiaan Wu, Dandan Wang, Xiaoyan Huang, Naining Zhang, Yikang Shi
Summary: The study demonstrates that cisplatin enhances protein O-GlcNAcylation by altering the activity of OGT, OGA, and AMPK in lung cancer cells both in vitro and in vivo. The findings also show that cisplatin treatment results in increased global protein O-GlcNAc levels, upregulated expression of OGT and OGA, and inhibited AMPK activity in the cells. Additionally, decreased AMPK activation inhibits GFAT1 phosphorylation and promotes its activity, leading to elevated UDP-GlcNAc production.
INTERNATIONAL JOURNAL OF ONCOLOGY
(2021)
Article
Multidisciplinary Sciences
Zebulon G. Levine, Sarah C. Potter, Cassandra M. Joiner, George Q. Fei, Behnam Nabet, Matthew Sonnett, Natasha E. Zachara, Nathanael S. Gray, Joao A. Paulo, Suzanne Walker
Summary: O-GlcNAc transferase (OGT) is crucial for cell proliferation, with its glycosyl-transferase function essential for cell growth while its protease function is dispensable. OGT also plays an essential noncatalytic role in cell proliferation, with its noncatalytic functions affecting different proteins from its catalytic functions.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Adam Kositzke, Dacheng Fan, Ao Wang, Hao Li, Matthew Worth, Jiaoyang Jiang
Summary: The essential human enzyme O-Linked beta-N-acetylglucosamine transferase (OGT) and O-GlcNAcase (OGA) play important roles in modifying intracellular proteins. Screening OGT TPR mutants revealed key residues affecting OGA O-GlcNAcylation. This study is the first to systematically investigate each OGT TPR, providing insights into the binding mechanism of OGT to OGA protein substrates.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2021)
Article
Biochemistry & Molecular Biology
Xiaoyan Li, Zhengming Wu, Jing He, Yiting Jin, Chengyu Chu, Yun Cao, Fei Gu, Hongying Wang, Chenjian Hou, Xiuping Liu, Qiang Zou
Summary: The incidence of thyroid cancer is increasing globally, with poor prognosis associated with distant metastases. OGT and YAP play critical roles in papillary thyroid cancer, suggesting potential for targeted therapies.
Article
Oncology
Chia-Hung Lin, Chen-Chung Liao, Shu-Ying Wang, Chia-Yi Peng, Yi-Chen Yeh, Mei-Yu Chen, Teh-Ying Chou
Summary: Lung cancer is the most deadly type of cancer, and invasion and metastasis are major challenges in its treatment. O-GlcNAcylation, a protein modification process, is linked to cancer pathogenesis, including invasion and metastasis. However, little is known about O-GlcNAcylated proteins involved in cancer aggressiveness. In this study, we compared the profiles of O-GlcNAcylated proteins in two lung cancer cell lines with different invasive potentials and identified potential candidates involved in cancer aggressiveness. Further characterization of one candidate, SAM68, confirmed its O-GlcNAcylation and suggested its role in regulating lung cancer cell migration and invasion. Our findings provide new insights into the mechanisms of lung cancer progression through O-GlcNAcylated proteins.
Article
Biochemistry & Molecular Biology
Xiaoqun Shan, Rong Jiang, Dongmei Gou, Jin Xiang, Peng Zhou, Jie Xia, Kai Wang, Ailong Huang, Ni Tang, Luyi Huang
Summary: O-GlcNAcylation is a crucial cellular process that is involved in various physiological processes. OGT is the only enzyme responsible for transferring O-GlcNAc to nucleocytoplasmic proteins. Abnormal glycosylation by OGT is associated with multiple diseases. This study identified a novel diketopiperazine-based OGT inhibitor called HLY838, which effectively decreases cellular O-GlcNAc levels and enhances the anti-HCC activity of CDK9 inhibitor by regulating c-Myc and E2F1 expression. These findings suggest the potential of OGT inhibitors as sensitizing agents in cancer therapeutics.
Article
Biochemistry & Molecular Biology
Elena M. Loi, Tihomir Tomasic, Cyril Balsollier, Kevin van Eekelen, Matjaz Weiss, Martina Gobec, Matthew G. Alteen, David J. Vocadlo, Roland J. Pieters, Marko Anderluh
Summary: In this study, a novel OGT inhibitor with a uridine mimetic scaffold was identified through virtual screening. The inhibitor showed promising activity in enzyme assays and provides a potential starting point for the development of OGT inhibitors with clinical applications.
Article
Oncology
Lianghao Zhai, Xiaoshan Yang, Jian Dong, Luomeng Qian, Yunge Gao, Yanhong Lv, Ligang Chen, Biliang Chen, Fuxing Zhou
Summary: The incidence of endometrial cancer (EC) is increasing globally. The study aimed to investigate the effects of O-GlcNAcylation on EC malignancy and its association with YAP. It was found that O-GlcNAc transferase (OGT) and O-GlcNAcylation were increased in EC tissues, and reducing O-GlcNAcylation levels decreased the proliferation, migration, and invasion of EC cells. Knockdown of OGT reduced the O-GlcNAcylation of YAP, which promoted its phosphorylation, inhibited YAP's nuclear access and downstream target gene activation, demonstrating that the level of O-GlcNAcylation affects EC development.
INTERNATIONAL JOURNAL OF ONCOLOGY
(2023)
Review
Oncology
Harri M. Itkonen, Massimo Loda, Ian G. Mills
Summary: OGT enzyme is involved in the posttranslational modification of serine and threonine residues, and its increased expression is a common feature in most human cancers. Inhibition of OGT reduces cancer cell proliferation by affecting known regulators of cancer cell proliferation. While OGT has potential in cancer therapy, further understanding of its substrate specificity and development of more specific inhibitors are needed.
MOLECULAR CANCER RESEARCH
(2021)
Article
Oncology
Satu Pallasaho, Aishwarya Gondane, Anni Kuivalainen, Samuel Girmay, Siver Moestue, Massimo Loda, Harri M. Itkonen
Summary: The study reveals that CDK7 and CDK9 are highly active in castration-resistant prostate cancer (CRPC) cells, and inhibiting these kinases can effectively suppress the proliferation of CRPC cells.
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
(2023)
Article
Chemistry, Medicinal
John Janetzko, Cory P. Johnson, Paula Morales, Magdalena M. Scharf
Summary: The second Transatlantic Early Career Investigator (ECI) GPCR Symposium aimed to provide a platform for young GPCR investigators to share research and network. This article discusses the format, impact, and future challenges and opportunities of such meetings.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Hematology
Joshua Bennett, Chiharu Ishikawa, Puneet Agarwal, Jennifer Yeung, Avery Sampson, Emma Uible, Eric Vick, Lyndsey C. Bolanos, Kathleen Hueneman, Mark Wunderlich, Amal Kolt, Kwangmin Choi, Andrew Volk, Kenneth D. Greis, Jan Rosenbaum, Scott B. Hoyt, Craig J. Thomas, Daniel T. Starczynowski
Summary: This study reveals the functional compensation and complementation of IRAK1 in leukemic cells upon inhibition of IRAK4. Cotargeting IRAK1 and IRAK4 is necessary to suppress leukemic stem/progenitor cell function and induce differentiation. IRAK1 and IRAK4 maintain the undifferentiated state of MDS/AML LSPCs through noncanonical MyD88-independent pathways.
Article
Oncology
Tyler J. Peat, Snehal M. Gaikwad, Wendy Dubois, Nana Gyabaah-Kessie, Shuling Zhang, Sayeh Gorjifard, Zaw Phyo, Megan Andres, Keith Hughitt, R. Mark Simpson, Margaret A. Miller, Andrew T. Girvin, Andrew Taylor, Daniel Williams, Nelson D'Antonio, Yong Zhang, Adhithi Rajagopalan, Evan Flietner, Kelli Wilson, Xiaohu Zhang, Paul Shinn, Carleen Klumpp-Thomas, Crystal McKnight, Zina Itkin, Lu Chen, Dickran Kazandijian, Jing Zhang, Aleksandra M. Michalowski, John K. Simmons, Jonathan Keats, Craig J. Thomas, Beverly A. Mock
Summary: Drug resistance and disease progression are common in MM patients. A study identified 43 potentially synergistic combinations through drug screening and in silico analysis. These combinations effectively reduce MYC expression and enhance p16 activity, leading to improved viability and prolonged survival in MM models.
Article
Oncology
Sebastian Scheich, Jiji Chen, Jiamin Liu, Frank Schnutgen, Julius C. Enssle, Michele Ceribelli, Craig J. Thomas, Jaewoo Choi, Vivian Morris, Tony Hsiao, Hang Nguyen, Boya Wang, Arnold Bolomsky, James D. Phelan, Sean Corcoran, Henning Urlaub, Ryan M. Young, Bjorn Haupl, George W. Wright, Da Wei Huang, Yanlong Ji, Xin Yu, Weihong Xu, Yandan Yang, Hong Zhao, Jagan Muppidi, Kuan-Ting Pan, Thomas Oellerich, Louis M. Staudt
Summary: Diffuse large B-cell lymphoma (DLBCL) can be categorized into two subtypes: activated B-cell (ABC) and germinal center B cell-like (GCB). The study found that self-antigen engagement of B-cell receptors (BCR) in ABC tumors triggers clustering, activating chronic active signaling and NF-KB and PI3 kinase. Genome-wide CRISPR-Cas9 screens were used to identify regulators of IRF4, a direct transcriptional target of NF-KB and an indicator of proximal BCR signaling in ABC DLBCL. Inactivation of N-linked protein glycosylation by the OST-B complex reduced IRF4 expression and targeting OST-B inhibition killed models of ABC and GCB DLBCL, suggesting the potential for selective OST-B inhibitors in treating these aggressive cancers.
Article
Biochemistry & Molecular Biology
David B. Morse, Aleksandra M. Michalowski, Michele Ceribelli, Joachim De Jonghe, Maria Vias, Deanna Riley, Theresa Davies-Hill, Ty Voss, Stefania Pittaluga, Christoph Muus, Jiamin Liu, Samantha Boyle, David A. Weitz, James D. Brenton, Jason D. Buenrostro, Tuomas P. J. Knowles, Craig J. Thomas
Summary: Single-cell RNA sequencing (scRNA-seq) is used to describe cell states, but the spatial arrangement of these states in tissues is challenging. Segmentation by exogenous perfusion (SEEP) is a method that links surface proximity and environment accessibility to transcriptional identity within 3D disease models. Using SEEP, analysis of ovarian cancer models reveals the relationship between cell state and position, and shows how microenvironments influence individual cell identities.
Article
Biochemical Research Methods
Emma J. Chory, Meng Wang, Michele Ceribelli, Aleksandra M. Michalowska, Stefan Golas, Erin Beck, Carleen Klumpp-Thomas, Lu Chen, Crystal McKnight, Zina Itkin, Kelli M. Wilson, David Holland, Sanjay Divakaran, James Bradner, Javed Khan, Berkley E. Gryder, Craig J. Thomas, Benjamin Z. Stanton
Summary: We conducted a comprehensive study on drug synergy in acute myeloid leukemia (AML), using a panel of cell lines representing different subtypes. Our study provides a valuable resource for the community, offering many unexpected synergistic drug combinations and open source code for automation and analysis. We identified drug synergies that affect the chromatin state, particularly in relation to the modification of histone H3 lysine-27. Additionally, we developed an open source high throughput methodology that allows multidimensional drug screening with widely accessible equipment.
Article
Medicine, Research & Experimental
Anju Kumari, Lisa Gesumaria, Yan-Jin Liu, V. Keith Hughitt, Xiaohu Zhang, Michele Ceribelli, Kelli M. Wilson, Carleen Klumpp-Thomas, Lu Chen, Crystal McKnight, Zina Itkin, Craig J. Thomas, Beverly A. Mock, David S. Schrump, Haobin Chen
Summary: Small cell lung cancer (SCLC) is a difficult-to-treat malignancy and current treatment options are limited. This study identified that mTOR inhibitors (mTORis) show the highest synergy with BET inhibitors (BETis) in SCLC, enhancing their antitumor activities both in vitro and in vivo. Mechanistically, BETis induce apoptosis in SCLC by activating the intrinsic apoptotic pathway, but also upregulate RSK3 to promote survival. However, mTORis block this survival signaling and augment the apoptosis induced by BET inhibition. Combination therapy of mTORis and BETis has potential for further evaluation in SCLC patients.
Article
Chemistry, Analytical
Steven R. Shuken, Graeme C. McAlister, William D. Barshop, Jesse D. Canterbury, David Bergen, Jingjing Huang, Romain Huguet, Joao A. Paulo, Vlad Zabrouskov, Steven P. Gygi, Qing Yu
Summary: The combination of tandem mass tags (TMT) and tribrid mass spectrometers provides high quantitative accuracy in high-throughput proteomics. The new Orbitrap Ascend mass spectrometer improves sensitivity and speed, allowing for the identification and quantification of more proteins.
ANALYTICAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Kelsey L. Hickey, Sharan Swarup, Ian R. Smith, Julia C. Paoli, Enya Miguel Whelan, Joao A. Paulo, J. Wade Harper
Summary: This study provides insights into the selectivity of macroautophagy for recycling membrane-bound organelles and identifies YIPF3 and YIPF4 as receptors for Golgiphagy. The findings also highlight the importance of these receptors in Golgi remodelling during neuronal differentiation.
Article
Biochemical Research Methods
Joel S. Gygi, Xinyue. Liu, Benjamin P. Levi, Joao A. Paulo
Summary: The study investigates the impact of dysfunction in the GET pathway on protein abundance in yeast deletion strains. The findings reveal differential abundance of certain proteins in the deletion strains, some of which are membrane-associated, while the abundance of many tail-anchored proteins remains unchanged. This study provides valuable insights into the roles of GET genes and alternative pathways that maintain cellular function despite disruption of the GET pathway.
Article
Multidisciplinary Sciences
Nishanth Ulhas Nair, Patricia Greninger, Xiaohu Zhang, Adam A. Friedman, Arnaud Amzallag, Eliane Cortez, Avinash Das Sahu, Joo Sang Lee, Anahita Dastur, Regina K. Egan, Ellen Murchie, Michele Ceribelli, Giovanna S. Crowther, Erin Beck, Joseph McClanaghan, Carleen Klump-Thomas, Jessica L. Boisvert, Leah J. Damon, Kelli M. Wilson, Jeffrey Ho, Angela Tam, Crystal McKnight, Sam Michael, Zina Itkin, Mathew J. Garnett, Jeffrey A. Engelman, Daniel A. Haber, Craig J. Thomas, Eytan Ruppin, Cyril H. Benes
Summary: Combination of anti-cancer drugs is commonly used to overcome limited efficacy of single agents. Designing and testing combinations are challenging due to the heterogeneity of tumor response. Co-targeting functionally proximal genes may result in higher efficacy, offering a strategy for more efficient combinations.
NATURE COMMUNICATIONS
(2023)
Article
Oncology
Jerry T. Wu, Adam Cheuk, Kristine Isanogle, Christina Robinson, Xiaohu Zhang, Michele Ceribelli, Erin Beck, Paul Shinn, Carleen Klumpp-Thomas, Kelli M. Wilson, Crystal Mcknight, Zina Itkin, Hiroshi Sotome, Hiroshi Hirai, Elizabeth Calleja, Volker Wacheck, Brad Gouker, Cody J. Peer, Natalia Corvalan, David Milewski, Yong Y. Kim, William D. Figg, Elijah F. Edmondson, Craig J. Thomas, Simone Difilippantonio, Jun S. Wei, Javed Khan
Summary: Rhabdomyosarcoma (RMS) is a common pediatric soft tissue sarcoma. Futibatinib, an irreversible pan-FGFR inhibitor, shows efficacy in inhibiting the growth of RMS cell lines in vitro by targeting FGFR4. However, limited efficacy is observed in animal models, suggesting the need for alternative treatment strategies.
Review
Biochemistry & Molecular Biology
Aishwarya Gondane, Harri M. Itkonen
Summary: Advancements in RNA-sequencing technologies have resulted in the development of diverse experimental setups and a massive accumulation of data, leading to a high demand for data analysis tools. Computational scientists have developed numerous analysis pipelines, but the selection of the most appropriate one is often overlooked. The RNA-sequencing data analysis pipeline consists of three major components: data pre-processing, main analysis, and downstream analysis. This article provides an overview of the tools used in bulk RNA-seq and single-cell RNA-seq, with a focus on alternative splicing and active RNA synthesis analysis. Quality control is essential in data pre-processing, determining the need for adapter removal, trimming, and filtering. The processed data is then analyzed using various tools, including differential gene expression, alternative splicing, and assessment of active synthesis, which requires dedicated sample preparation.
CURRENT ISSUES IN MOLECULAR BIOLOGY
(2023)
Article
Cell Biology
Selcan Aydin, Duy T. Pham, Tian Zhang, Gregory R. Keele, Daniel A. Skelly, Joao A. Paulo, Matthew Pankratz, Ted Choi, Steven P. Gygi, Laura G. Reinholdt, Christopher L. Baker, Gary A. Churchill, Steven C. Munger
Summary: This study comprehensively analyzed the proteome of genetically diverse mESC lines and found significant variability in protein abundance. It identified pluripotency-associated pathways that were not evident in transcriptome data from the same lines. Integration of protein abundance with transcript levels and chromatin accessibility revealed co-variation across molecular layers and identified drivers of quantitative variation in pluripotency-associated pathways.
