Article
Biochemistry & Molecular Biology
Susu Zhang, Jing Wang, Qi Liu, W. Hayes McDonald, Monica L. Bomber, Hillary M. Layden, Jacob Ellis, Scott C. Borinstein, Scott W. Hiebert, Kristy R. Stengel
Summary: Transcriptional control is a dynamic process that is challenging to study using traditional genetic methods. In this study, we used a chemical-genetic approach to quickly degrade the transcriptional activator PAX3-FOXO1 and investigated its mechanism of action. Our findings revealed that PAX3-FOXO1 is involved in regulating gene expression and maintaining chromatin accessibility and enhancer architecture.
Article
Genetics & Heredity
Line J. Manceau, Julien E. Richard Albert, Pier-Luigi J. Lollini, Maxim V. C. E. Greenberg, Pascale J. Gilardi-Hebenstreit, Vanessa E. Ribes
Summary: The chimeric proteins PAX3-FOXO1 and PAX7-FOXO1, derived from chromosomal translocations, exhibit distinct genomic occupancy and transcriptional activity, leading to different pathological manifestations in alveolar rhabdomyosarcoma.
Article
Pediatrics
Weifeng Zhang, Yanru Chen, Chunmei Lin, Weilin Peng, Qingliu Fu, Yiming Lin
Summary: The incidence of CPT1A deficiency in the Chinese population was estimated to be 1:102,388. Among 12 patients identified in the study, 5 were diagnosed via newborn screening and 7 presented with clinical symptoms. A total of 18 distinct CPT1A variants were identified, with 3 novel variants potentially pathogenic.
FRONTIERS IN PEDIATRICS
(2021)
Article
Medicine, Research & Experimental
Wenyan Su, Zuoyu Hu, Xiaohong Zhong, Ansheng Cong, Ying Zhang, Zhanmei Zhou, Jianyi Li, Cailing Su, Yujie Huang, Wei Cao
Summary: This study found that the fibrosis in peritoneal dialysis patients is associated with decreased fatty acid oxidation and carnitine palmitoyltransferase 1A expression. Overexpression of carnitine palmitoyltransferase 1A can reverse the fibrosis process.
Article
Reproductive Biology
Na Li, Rufei Gao, Xuemei Chen, Xueqing Liu, Yubin Ding, Junlin He, Fangfang Li, Xianqing Cao, Chengshun Yang, Yingxiong Wang
Summary: CPT1A plays a crucial role in decidualization during early pregnancy by regulating stromal cell proliferation. The study revealed a significant increase in CPT1A expression on days 5-7 of pregnancy, showing a positive impact on artificially induced decidualization.
Article
Biology
Carla Regina, Ebrahem Hamed, Geoffroy Andrieux, Sina Angenendt, Michaela Schneider, Manching Ku, Marie Follo, Marco Wachtel, Eugene Ke, Ken Kikuchi, Anton G. Henssen, Beat W. Schafer, Melanie Boerries, Amy J. Wagers, Charles Keller, Simone Hettmer
Summary: The study shows that heterogeneous expression of PAX3:FOXO1 at the single cell level in rhabdomyosarcoma cells may provide a critical advantage during tumor progression.
LIFE SCIENCE ALLIANCE
(2021)
Article
Medicine, Research & Experimental
Lifang Li, Yaqian Zhang, Jiannan Gong, Guang Yang, Shuyin Zhi, Dongping Ren, Hui Zhao
Summary: The study aimed to determine the expression of Cpt1a in the lung tissue of COPD patients and its correlation with lung function. Increased Cpt1a expression improved lung function in patients with COPD by inhibiting apoptosis and inflammation in lung endothelial cells. In vivo and in vitro experiments confirmed that Cpt1a attenuated lung dysfunction in COPD by inhibiting endothelial cell apoptosis and inflammatory responses.
EXPERIMENTAL AND THERAPEUTIC MEDICINE
(2023)
Article
Oncology
Seo Jin Kim, Soo Jeong Park, Junseong Park, Hye Joung Cho, Jin-Kyoung Shim, Jieun Seon, Ran Joo Choi, Seon-Jin Yoon, Ju Hyung Moon, Eui Hyun Kim, Eui Kyo Seo, Sun Ho Kim, Hyun Sil Kim, Wan-Yee Teo, Jong Hee Chang, Jong In Yook, Seok-Gu Kang
Summary: The study evaluated the therapeutic effects and underlying mechanisms of dual inhibition of CPT1A and G6PD in GBM, and found that this treatment approach effectively suppressed tumor growth and invasion, and extended survival in GBM mice models.
JOURNAL OF NEURO-ONCOLOGY
(2022)
Article
Oncology
Christine M. Heske, Yueh-Yun Chi, Rajkumar Venkatramani, Minjie Li, Michael A. Arnold, Roshni Dasgupta, Susan M. Hiniker, Douglas S. Hawkins, Leo Mascarenhas
Summary: In patients with localized, FOXO1 fusion-positive RMS, clinical factors such as age at diagnosis and tumor size can impact survival outcomes, with older age and larger tumors being adverse prognostic factors for EFS. Patients with both older age and large tumor size experience significantly inferior outcomes.
Article
Gastroenterology & Hepatology
Peng Wang, Ruikai Li, Yuqi Li, Siwei Tan, Jie Jiang, Huiling Liu, Xiuqing Wei
Summary: Berberine effectively alleviates non-alcoholic fatty liver disease (NAFLD) by promoting the deacetylation of CPT1A through SIRT1, thereby reducing its degradation and improving lipid metabolism.
GASTROENTEROLOGY REPORT
(2023)
Article
Genetics & Heredity
Qingwen Ren, Mengzhu Guo, Feifei Yang, Tianbi Han, Wenqiong Du, Feng Zhao, Jinbo Li, Wangjun Li, Yongliang Feng, Suping Wang, Yawei Zhang, Weiwei Wu
Summary: The study found that certain single-nucleotide polymorphisms (SNPs) in the CPT1A gene were associated with both increased and decreased risk of gestational diabetes mellitus (GDM). Additionally, a specific haplotype in the CPT1A gene was linked to a reduced risk of GDM.
JOURNAL OF ASSISTED REPRODUCTION AND GENETICS
(2021)
Article
Immunology
Yan Xue, Hui Liu, Xin-Xiang Yang, Li Pang, Jiang Liu, Kevin T. P. Ng, Oscar W. H. Yeung, Yin-Fan Lam, Wei-Yi Zhang, Chung-Mau Lo, Kwan Man
Summary: The study indicates that reduced expression of CPT1A in fatty liver transplantation is significantly associated with liver dysfunction. While inhibition of CPT1A may trigger MPT and worsen cell damage, activation of CPT1A could potentially attenuate hepatic IRI in fatty liver grafts.
Article
Biochemistry & Molecular Biology
Yuling Zhao, Haixia Feng, Ying Wang, Lu Jiang, Junkai Yan, Wei Cai
Summary: This study discovered that villus atrophy is a major cause of intestinal failure in children with short bowel syndrome (SBS) who receive parenteral nutrition (PN), but the mechanism is unclear. The study demonstrated the crucial role of farnesoid X receptor (FXR) signaling and fatty acid oxidation (FAO) in PN-induced villus atrophy. Impaired FXR/CPT1a axis and disturbed FAO may play a pivotal role in PN-induced villus atrophy, contributing to intestinal failure in SBS patients.
Article
Oncology
Daniela Di Carlo, Cyrus Chargari, Jean-Yves Scoazec, Sophie Cotteret, Arthur Felix, Salma Moalla, Stephane Temam, Veronique Minard-Colin
Summary: Alveolar rhabdomyosarcoma (ARMS) is commonly associated with PAX3/PAX7-FOXO1 fusion gene, but some tumors without this fusion may have new molecular alterations. A rare case of PAX3-NCOA1 ARMS in a two-year-old girl with tongue and nodal extension was treated with a combination of therapies to preserve oral function and minimize long-term effects. International collaboration is necessary to evaluate the prognostic value of this variant fusion in ARMS.
PEDIATRIC BLOOD & CANCER
(2021)
Article
Gastroenterology & Hepatology
Robert N. Helsley, Se-Hyung Park, Hemendra J. Vekaria, Patrick G. Sullivan, Lindsey R. Conroy, Ramon C. Sun, Maria del Mar Romero, Laura Herrero, Joanna Bons, Christina D. King, Jacob Rose, Jesse G. Meyer, Birgit Schilling, C. Ronald Kahn, Samir Softic
Summary: The consumption of sugar and a high-fat diet promotes the development of obesity and metabolic dysfunction. The study found that glucose or fructose supplementation increases the enzyme KHK-C, which leads to abnormal lipogenesis. The researchers also discovered that KHK-C increases lipogenesis and decreases fatty acid oxidation by acetylating CPT1a protein. This finding reveals the mechanism by which dietary fructose exacerbates metabolic complications caused by a high-fat diet.
JOURNAL OF HEPATOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Yiannis Drosos, Jacquelyn A. Myers, Beisi Xu, Kaeli M. Mathias, Emma C. Beane, Sandi Radko-Juettner, Robert J. Mobley, Margaret E. Larsen, Federica Piccioni, Xiaotu Ma, Jonathan Low, Baranda S. Hansen, Samuel T. Peters, Natarajan Bhanu, Sandeep K. Dhanda, Taosheng Chen, Santhosh A. Upadhyaya, Shondra M. Pruett-Miller, David E. Root, Benjamin A. Garcia, Janet F. Partridge, Charles W. M. Roberts
Summary: Disruption of antagonism between SWI/SNF chromatin remodelers and polycomb repressor complexes drives the formation of numerous cancer types. Loss of the H3K36 methyltransferase NSD1 causes resistance to EZH2 inhibition. H3K36me2 itself has an essential role in the activation of polycomb target genes.
Article
Biochemistry & Molecular Biology
Monicah N. Bwayi, Efren Garcia-Maldonado, Sergio C. Chai, Boer Xie, Shirish Chodankar, Andrew D. Huber, Jing Wu, Kavya Annu, William C. Wright, Hyeong-Min Lee, Jayaraman Seetharaman, Jingheng Wang, Cameron D. Buchman, Junmin Peng, Taosheng Chen
Summary: The interactions between nuclear receptors can fundamentally change our understanding of their biology. In this study, the molecular basis of crosstalk between the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) is revealed, demonstrating the formation of a novel heterodimer and mutual inhibition. These findings not only change the perceived functional relationship between PXR and CAR, but also provide new perspectives for elucidating their role and designing approaches to regulate them.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Huan Sun, Ka Yang, Xue Zhang, Yingxue Fu, Jay Yarbro, Zhiping Wu, Ping-Chung Chen, Taosheng Chen, Junmin Peng
Summary: Chemoproteomics is a crucial platform for studying the mode of action of compounds. This study presents a pooling strategy to enhance throughput and applies it to a drug library. The findings demonstrate that pooling chemoproteomics screening is an efficient method for dissecting the molecular targets of compound libraries.
Article
Cell Biology
Shivendra Singh, Ahmed Abu-Zaid, Hongjian Jin, Jie Fang, Qiong Wu, Tingting Wang, Helin Feng, Waise Quarni, Ying Shao, Lily Maxham, Alireza Abdolvahabi, Mi-Kyung Yun, Sivaraja Vaithiyalingam, Haiyan Tan, John Bowling, Victoria Honnell, Brandon Young, Yian Guo, Richa Bajpai, Shondra M. Pruett-Miller, Gerard C. Grosveld, Mark Hatley, Beisi Xu, Yiping Fan, Gang Wu, Eleanor Y. Chen, Taosheng Chen, Peter W. Lewis, Zoran Rankovic, Yimei Li, Andrew J. Murphy, John Easton, Junmin Peng, Xiang Chen, Ruoning Wang, Stephen W. White, Andrew M. Davidoff, Jun Yang
Summary: This study identifies KDM4B as a therapeutic vulnerability for PAX3-FOXO1(+) RMS. Inhibition of KDM4B delays tumor growth and suppresses the expression of core oncogenic transcription factors, causing epigenetic alterations of PAX3-FOXO1-governed superenhancers.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Article
Chemistry, Medicinal
Andrew D. Huber, Yongtao Li, Wenwei Lin, Annalise N. Galbraith, Ashutosh Mishra, Shaina N. Porter, Jing Wu, Rebecca R. Florke Gee, Wei Zhuang, Shondra M. Pruett-Miller, Junmin Peng, Taosheng Chen
Summary: This study describes the discovery of a molecule, SJPYT-195, which can reduce the protein level of PXR by acting as a molecular glue degrader of GSPT1, a translation termination factor. The findings provide insights into the chemical determinants of drug-induced GSPT1 degradation and also present assays and cell models for the discovery of PXR degraders.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Review
Pharmacology & Pharmacy
Shyaron Poudel, Andrew D. Huber, Taosheng Chen
Summary: PXR and CAR are ligand-activated transcription factors that regulate drug metabolizing enzymes and transporters. They not only play important roles in drug efficacy, toxicity, and interactions, but also respond to a wide range of stimuli and are implicated in various diseases. Recent research has provided new insights into their biology and potential clinical applications.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Chemistry, Medicinal
Anand Divakaran, Cole R. Scholtz, Huda Zahid, Wenwei Lin, Elizabeth C. Griffith, Richard E. Lee, Taosheng Chen, Daniel A. Harki, William C. K. Pomerantz
Summary: Targeted protein degradation is a powerful tool for controlling cellular protein concentrations. In this study, the researchers designed a selective inhibitor of the first BRD4 bromodomain and developed a selective degrader for BRD4. This approach allowed for specific degradation of BRD4 without inhibiting other BET family members such as BRD2/3.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Multidisciplinary Sciences
Giridhar Sekar, Geetika Singh, Xingping Qin, Cristina D. Guibao, Brittany Schwam, Zintis Inde, Christy R. Grace, Weixing Zhang, P. Jake Slavish, Wenwei Lin, Taosheng Chen, Richard E. Lee, Zoran Rankovic, Kristopher Sarosiek, Tudor Moldoveanu
Summary: The small molecule SJ572946 selectively activates BAK over BAX, showing cytotoxic effects on cancer cells, and can be used in combination with other apoptotic inducers and BH3 mimetics.
Article
Multidisciplinary Sciences
Wenwei Lin, Andrew D. Huber, Shyaron Poudel, Yongtao Li, Jayaraman Seetharaman, Darcie J. Miller, Taosheng Chen
Summary: The promiscuity of ligand-binding in detoxification systems is beneficial for body protection but a challenge for drug development. Through X-ray crystallography, we found that expanding the ligand-binding pocket of the PXR receptor can enhance binding affinity. However, this expansion is an unfavorable event, and engineering ligands to avoid clashes with the receptor can reduce safety liabilities. Therefore, engineering the ligand-binding pocket of PXR can potentially improve drug development.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Jennifer L. Kamens, Stephanie Nance, Cary Koss, Beisi Xu, Anitria Cotton, Jeannie W. Lam, Elizabeth A. R. Garfinkle, Pratima Nallagatla, Amelia M. R. Smith, Sharnise Mitchell, Jing Ma, Duane Currier, William C. Wright, Kanisha Kavdia, Vishwajeeth R. Pagala, Wonil Kim, LaShanale M. Wallace, Ji-Hoon Cho, Yiping Fan, Aman Seth, Nathaniel Twarog, John K. Choi, Esther A. Obeng, Mark E. Hatley, Monika L. Metzger, Hiroto Inaba, Sima Jeha, Jeffrey E. Rubnitz, Junmin Peng, Taosheng Chen, Anang A. Shelat, R. Kiplin Guy, Tanja A. Gruber
Summary: Proteasome inhibition is found to be effective in KMT2Ar infant acute lymphoblastic leukemia, leading to the depletion of histone modifications and downregulation of KMT2A gene expression signature. A cohort of relapsed/refractory KMT2Ar patients treated with this approach showed a high overall response rate. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Giovanni Quarato, Luigi Mari, Nicholas J. Barrows, Mao Yang, Sebastian Ruehl, Mark J. Chen, Cliff S. Guy, Jonathan Low, Taosheng Chen, Douglas R. Green
Summary: The degradation of defective mitochondria is regulated by the ubiquitin-proteasome system and lysosomal activities, which play essential roles in maintaining cellular homeostasis. Activation of the PINK1-Parkin axis following mitochondrial damage triggers a BAX- and BAK-independent cytochrome c release process, leading to apoptosis mediated by APAF1 and caspase 9. This process is initiated by UPS-dependent outer mitochondrial membrane degradation and can be reversed by proteasome inhibitors. Autophagy machinery recruitment to the outer mitochondrial membrane protects cells from apoptosis by mediating the lysosomal degradation of dysfunctional mitochondria. The study highlights the major role of the autophagy machinery in counteracting abnormal noncanonical apoptosis and identifies autophagy receptors as key regulators of this process.
Article
Oncology
Mika B. Jekabsons, Mollie Merrell, Anna G. Skubiz, Noah Thornton, Sandra Milasta, Douglas Green, Taosheng Chen, Yan-Hong Wang, Bharathi Avula, Ikhlas A. Khan, Yu-Dong Zhou
Summary: Gene expression signatures associated with breast cancer metastases suggest that metabolic re-wiring is important for metastatic growth in lungs, bones, and other organs. Flux analysis is necessary to conclusively establish phenotypes, as pathway fluxes depend on additional factors. This study assessed the metabolic phenotypes of breast cancer cell lines with different metastatic potentials, as well as lung and bone-homing lines, and found differences in ATP production, nutrient consumption, and anabolic fluxes.
CANCER & METABOLISM
(2023)
Article
Multidisciplinary Sciences
Jie Fang, Shivendra Singh, Changde Cheng, Sivaraman Natarajan, Heather Sheppard, Ahmed Abu-Zaid, Adam D. Durbin, Ha Won Lee, Qiong Wu, Jacob Steele, Jon P. Connelly, Hongjian Jin, Wenan Chen, Yiping Fan, Shondra M. Pruett-Miller, Jerold E. Rehg, Selene C. Koo, Teresa Santiago, Joseph Emmons, Stefano Cairo, Ruoning Wang, Evan S. Glazer, Andrew J. Murphy, Taosheng Chen, Andrew M. Davidoff, Carolina Armengol, John Easton, Xiang Chen, Jun Yang
Summary: A improved MYC-driven hepatoblastoma-like murine model is developed and characterized in this study, which recapitulates the pathological features of embryonal type of hepatoblastoma and shows transcriptomics resembling the high-risk gene signatures of the human disease. Single-cell RNA-sequencing and CRISPR-Cas9 screening are used to identify distinct subpopulations of hepatoblastoma cells and druggable targets shared with human hepatoblastoma. The study also reveals genetic modifiers of chemotherapy response and suggests a potential therapeutic strategy for human hepatoblastoma.
NATURE COMMUNICATIONS
(2023)
Article
Pharmacology & Pharmacy
Rebecca R. Florke Gee, Andrew D. Huber, Jing Wu, Richa Bajpai, Allister J. Loughran, Shondra M. Pruett-Miller, Taosheng Chen
Summary: This study identified FBXO44 as a novel E3 ligase for PXR, which regulates the protein abundance of PXR and has downstream effects on CYP3A4 levels and drug-drug interactions.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Cell Biology
Ping-Chung Chen, Xian Han, Timothy I. Shaw, Yingxue Fu, Huan Sun, Mingming Niu, Zhen Wang, Yun Jiao, Brett J. W. Teubner, Donnie Eddins, Lauren N. Beloate, Bing Bai, Joseph Mertz, Yuxin Li, Ji-Hoon Cho, Xusheng Wang, Zhiping Wu, Danting Liu, Suresh Poudel, Zuo-Fei Yuan, Ariana Mancieri, Jonathan Low, Hyeong-Min Lee, Mary H. Patton, Laurie R. Earls, Elizabeth Stewart, Peter Vogel, Yawei Hui, Shibiao Wan, David A. Bennett, Geidy E. Serrano, Thomas G. Beach, Michael A. Dyer, Richard J. Smeyne, Tudor Moldoveanu, Taosheng Chen, Gang Wu, Stanislav S. Zakharenko, Gang Yu, Junmin Peng
Summary: The study reveals the causative role of U1 snRNP dysfunction to neurodegeneration in Alzheimer's disease and demonstrates the synergy between RNA splicing defect and amyloid cascade. By generating a mouse model with perturbed U1 snRNP activity, the authors recapitulate RNA splicing defects, neuron hyperexcitability, neurodegeneration, and cognitive decline.
