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Markey Cancer Center Faculty Publications

Articles 61 - 81 of 81

Full-Text Articles in Biochemistry

A Kinome-Wide Crispr Screen Identifies Ck1Α As A Target To Overcome Enzalutamide Resistance Of Prostate Cancer, Jinghui Liu, Yue Zhao, Daheng He, Katelyn M. Jones, Shan Tang, Derek B. Allison, Yanquan Zhang, Jing Chen, Qiongsi Zhang, Xinyi Wang, Chaohao Li, Chi Wang, Lang Li, Xiaoqi Liu Apr 2023

A Kinome-Wide Crispr Screen Identifies Ck1Α As A Target To Overcome Enzalutamide Resistance Of Prostate Cancer, Jinghui Liu, Yue Zhao, Daheng He, Katelyn M. Jones, Shan Tang, Derek B. Allison, Yanquan Zhang, Jing Chen, Qiongsi Zhang, Xinyi Wang, Chaohao Li, Chi Wang, Lang Li, Xiaoqi Liu

Markey Cancer Center Faculty Publications

Enzalutamide (ENZA), a second-generation androgen receptor antagonist, has significantly increased progression-free and overall survival of patients with metastatic prostate cancer (PCa). However, resistance remains a prominent obstacle in treatment. Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1a (CK1a) as a therapeutic target to overcome ENZA resistance. Depletion or pharmacologic inhibition of CK1a enhanced ENZA efficacy in ENZA-resistant cells and patient-derived xenografts. Mechanistically, CK1a phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of …

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Identification Of A Nacc1-Regulated Gene Signature Implicated In The Features Of Triple-Negative Breast Cancer, Chrispus Ngule, Hami Hemati, Xingcong Ren, Oluwafunminiyi Obaleye, Amos O. Akinyemi, Felix Oyelami, Xiaofang Xiong, Jianxun Song, Xia Liu, Jin-Ming Yang Apr 2023

Identification Of A Nacc1-Regulated Gene Signature Implicated In The Features Of Triple-Negative Breast Cancer, Chrispus Ngule, Hami Hemati, Xingcong Ren, Oluwafunminiyi Obaleye, Amos O. Akinyemi, Felix Oyelami, Xiaofang Xiong, Jianxun Song, Xia Liu, Jin-Ming Yang

Markey Cancer Center Faculty Publications

Triple-negative breast cancer (TNBC), characterized by a deficiency in estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor2 (HER2), is among the most lethal subtypes of breast cancer (BC). Nevertheless, the molecular determinants that contribute to its malignant phenotypes such as tumor heterogeneity and therapy resistance, remain elusive. In this study, we sought to identify the stemness-associated genes involved in TNBC progression. Using bioinformatics approaches, we found 55 up- and 9 downregulated genes in TNBC. Out of the 55 upregulated genes, a 5 gene-signature (CDK1, EZH2, CCNB1, CCNA2, and AURKA) involved in cell regeneration was positively correlated …

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In Situ Microwave Fixation Provides An Instantaneous Snapshot Of The Brain Metabolome, Jelena A. Juras, Madison B. Webb, Lyndsay E. A. Young, Kia H. Markussen, Tara R. Hawkinson, Michael D. Buoncristiani, Kayli E. Bolton, Peyton T. Coburn, Meredith I. Williams, Lisa P. Y. Sun, William C. Sanders, Ronald C. Bruntz, Lindsey R. Conroy, Chi Wang, Matthew S. Gentry, Bret N. Smith, Ramon C. Sun Apr 2023

In Situ Microwave Fixation Provides An Instantaneous Snapshot Of The Brain Metabolome, Jelena A. Juras, Madison B. Webb, Lyndsay E. A. Young, Kia H. Markussen, Tara R. Hawkinson, Michael D. Buoncristiani, Kayli E. Bolton, Peyton T. Coburn, Meredith I. Williams, Lisa P. Y. Sun, William C. Sanders, Ronald C. Bruntz, Lindsey R. Conroy, Chi Wang, Matthew S. Gentry, Bret N. Smith, Ramon C. Sun

Markey Cancer Center Faculty Publications

Brain glucose metabolism is highly heterogeneous among brain regions and continues postmortem. In particular, we demonstrate exhaustion of glycogen and glucose and an increase in lactate production during conventional rapid brain resection and preservation by liquid nitrogen. In contrast, we show that these post- mortem changes are not observed with simultaneous animal sacrifice and in situ fixation with focused, high- power microwave. We further employ microwave fixation to define brain glucose metabolism in the mouse model of streptozotocin-induced type 1 diabetes. Using both total pool and isotope tracing analyses, we identified global glucose hypometabolism in multiple brain regions, evidenced by …

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Targeting Lncrna Ddit4-As1 Sensitizes Triple Negative Breast Cancer To Chemotherapy Via Suppressing Of Autophagy, Ting Jiang, Jiaojiao Zhu, Shilong Jiang, Zonglin Chen, Ping Xu, Rong Gong, Changxin Zhong, Yueying Cheng, Xinyuan Sun, Wenjun Yi, Jinming Yang, Wenhu Zhou, Yan Cheng Apr 2023

Targeting Lncrna Ddit4-As1 Sensitizes Triple Negative Breast Cancer To Chemotherapy Via Suppressing Of Autophagy, Ting Jiang, Jiaojiao Zhu, Shilong Jiang, Zonglin Chen, Ping Xu, Rong Gong, Changxin Zhong, Yueying Cheng, Xinyuan Sun, Wenjun Yi, Jinming Yang, Wenhu Zhou, Yan Cheng

Markey Cancer Center Faculty Publications

In this study, it is found that the lncRNA, DNA damage inducible transcript 4 antisense RNA1 (DDIT4-AS1), is highly expressed in triple-negative breast cancer (TNBC) cell lines and tissues due to H3K27 acetylation in the promoter region, and promotes the proliferation, migration, and invasion of TNBC cells via activating autophagy. Mechanistically, it is shown that DDIT4-AS1 induces autophagy by stabilizing DDIT4 mRNA via recruiting the RNA binding protein AUF1 and promoting the interaction between DDIT4 mRNA and AUF1, thereby inhibiting mTOR signaling pathway. Furthermore, silencing of DDIT4-AS1 enhances the sensitivity of TNBC cells to chemotherapeutic agents such as paclitaxel both …

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Loss Of Peroxiredoxin Iv Protects Mice From Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development, Pratik Thapa, Hong Jiang, Na Ding, Yanning Hao, Aziza Alshahrani, Eun Young Lee, Junichi Fujii, Qiou Wei Mar 2023

Loss Of Peroxiredoxin Iv Protects Mice From Azoxymethane/Dextran Sulfate Sodium-Induced Colorectal Cancer Development, Pratik Thapa, Hong Jiang, Na Ding, Yanning Hao, Aziza Alshahrani, Eun Young Lee, Junichi Fujii, Qiou Wei

Markey Cancer Center Faculty Publications

Peroxiredoxin IV (Prx4), a typical two-cysteine-containing member of the peroxidase family, functions as an antioxidant to maintain cellular redox homeostasis through the reduction of reactive oxygen species (ROS) via cycles of oxidation–reduction reactions. Under oxidative stress, all Prxs including Prx4 are inactivated as their catalytic cysteines undergo hyperoxidation, and hyperoxidized two-cysteine Prxs can be exclusively repaired and revitalized through the reduction cycle catalyzed by sulfiredoxin (Srx). Previously, we showed that Prx4 is a preferred substrate of Srx, and knockout of Srx in mice leads to resistance to azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon carcinogenesis. To further understand the significance of the …

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Latexin Regulates Sex Dimorphism In Hematopoiesis Via Gender-Specific Differential Expression Of Microrna 98-3p And Thrombospondin 1, Xiaojing Cui, Cuiping Zhang, Fang Wang, Xinghui Zhao, Shuxia Wang, Jinpeng Liu, Daheng He, Chi Wang, Feng-Chun Yang, Sheng Tong, Ying Liang Mar 2023

Latexin Regulates Sex Dimorphism In Hematopoiesis Via Gender-Specific Differential Expression Of Microrna 98-3p And Thrombospondin 1, Xiaojing Cui, Cuiping Zhang, Fang Wang, Xinghui Zhao, Shuxia Wang, Jinpeng Liu, Daheng He, Chi Wang, Feng-Chun Yang, Sheng Tong, Ying Liang

Markey Cancer Center Faculty Publications

Hematopoietic stem cells (HSCs) have the ability to self-renew and differentiate to all blood cell types. HSCs and their differentiated progeny show sex/gender differences. The fundamental mechanisms remain largely unexplored. We previously reported that latexin (Lxn) deletion increased HSC survival and repopulation capacity in female mice. Here, we find no differences in HSC function and hematopoiesis in Lxn knockout (Lxn-/- male mice under physiologic and myelosuppressive conditions. We further find that Thbs1, a downstream target gene of Lxn in female HSCs, is repressed in male HSCs. Male-specific high expression of micro- RNA 98-3p (miR98-3p) contributes to Thbs1 suppression in male …

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An Improved Germline Genome Assembly For The Sea Lamprey Petromyzon Marinus Illuminates The Evolution Of Germline-Specific Chromosomes, Nataliya Timoshevskaya, Kaan İ. Eşkut, Vladimir A. Timoshevskiy, Sofia M.C. Robb, Carson Holt, Jon E. Hess, Hugo J. Parker, Cindy F. Baker, Allison K. Miller, Cody Saraceno, Mark Yandell, Robb Krumlauf, Shawn R. Narum, Ralph T. Lampman, Neil J. Gemmell, Jacquelyn Mountcastle, Bettina Haase, Jennifer R. Balacco, Giulio Formenti, Sarah Pelan, Ying Sims, Kerstin Howe, Olivier Fedrigo, Erich D. Jarvis, Jeramiah James Smith Mar 2023

An Improved Germline Genome Assembly For The Sea Lamprey Petromyzon Marinus Illuminates The Evolution Of Germline-Specific Chromosomes, Nataliya Timoshevskaya, Kaan İ. Eşkut, Vladimir A. Timoshevskiy, Sofia M.C. Robb, Carson Holt, Jon E. Hess, Hugo J. Parker, Cindy F. Baker, Allison K. Miller, Cody Saraceno, Mark Yandell, Robb Krumlauf, Shawn R. Narum, Ralph T. Lampman, Neil J. Gemmell, Jacquelyn Mountcastle, Bettina Haase, Jennifer R. Balacco, Giulio Formenti, Sarah Pelan, Ying Sims, Kerstin Howe, Olivier Fedrigo, Erich D. Jarvis, Jeramiah James Smith

Markey Cancer Center Faculty Publications

Programmed DNA loss is a gene silencing mechanism that is employed by several vertebrate and nonvertebrate lineages, including all living jawless vertebrates and songbirds. Reconstructing the evolution of somatically eliminated (germline-specific) sequences in these species has proven challenging due to a high content of repeats and gene duplications in eliminated sequences and a corresponding lack of highly accurate and contiguous assemblies for these regions. Here, we present an improved assembly of the sea lamprey (Petromyzon marinus) genome that was generated using recently standardized methods that increase the contiguity and accuracy of vertebrate genome assemblies. This assembly resolves highly contiguous, somatically …

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Chalcone Derivative Cx258 Suppresses Colorectal Cancer Via Inhibiting The Top2a/Wnt/Β-Catenin Signaling, Xi Chen, Xiaocheng Lv, Lijie Gao, Jiawei Liu, Wei Wang, Lichao Guo, Mykhaylo S. Frasinyuk, Wen Zhang, David S. Watt, Chunming Liu, Xifu Liu Mar 2023

Chalcone Derivative Cx258 Suppresses Colorectal Cancer Via Inhibiting The Top2a/Wnt/Β-Catenin Signaling, Xi Chen, Xiaocheng Lv, Lijie Gao, Jiawei Liu, Wei Wang, Lichao Guo, Mykhaylo S. Frasinyuk, Wen Zhang, David S. Watt, Chunming Liu, Xifu Liu

Markey Cancer Center Faculty Publications

The deregulation in the Wnt/β-catenin signaling pathway is associated with many human cancers, particularly colorectal cancer (CRC) and, therefore, represents a promising target for drug development. We have screened over 300 semisynthetic and natural compounds using a Wnt reporter assay and identified a family of novel chalcone derivatives (CXs) that inhibited Wnt signaling and CRC cell proliferation. Among them, we selected CX258 for further in vitro and in vivo study to investigate the molecular mechanisms. We found that CX258 significantly inhibited β-catenin expression and nuclear translocation, inducing cell cycle arrest at the G2/M phase in CRC cells. Additionally, CX258 reduced …

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Endogenous Glycoprotein Gpm6a Is Involved In Neurite Outgrowth In Rat Dorsal Root Ganglion Neurons, Gabriela I. Aparicio, Antonella León, Rocío Gutiérrez Fuster, Baylen Ravenscraft, Paula V. Monje, Camila Scorticati Mar 2023

Endogenous Glycoprotein Gpm6a Is Involved In Neurite Outgrowth In Rat Dorsal Root Ganglion Neurons, Gabriela I. Aparicio, Antonella León, Rocío Gutiérrez Fuster, Baylen Ravenscraft, Paula V. Monje, Camila Scorticati

Markey Cancer Center Faculty Publications

The peripheral nervous system (PNS) has a unique ability for self-repair. Dorsal root ganglion (DRG) neurons regulate the expression of different molecules, such as neurotrophins and their receptors, to promote axon regeneration after injury. However, the molecular players driving axonal regrowth need to be better defined. The membrane glycoprotein GPM6a has been described to contribute to neuronal development and structural plasticity in central-nervous-system neurons. Recent evidence indicates that GPM6a interacts with molecules from the PNS, although its role in DRG neurons remains unknown. Here, we characterized the expression of GPM6a in embryonic and adult DRGs by combining analysis of public …

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Kegg_Pull: A Software Package For The Restful Access And Pulling From The Kyoto Encyclopedia Of Gene And Genomes, Erik D. Huckvale, Hunter N. B. Moseley Mar 2023

Kegg_Pull: A Software Package For The Restful Access And Pulling From The Kyoto Encyclopedia Of Gene And Genomes, Erik D. Huckvale, Hunter N. B. Moseley

Markey Cancer Center Faculty Publications

Background: The Kyoto Encyclopedia of Genes and Genomes (KEGG) provides organized genomic, biomolecular, and metabolic information and knowledge that is reasonably current and highly useful for a wide range of analyses and modeling. KEGG follows the principles of data stewardship to be findable, accessible, interoperable, and reusable (FAIR) by providing RESTful access to their database entries via their web-accessible KEGG API. However, the overall FAIRness of KEGG is often limited by the library and software package support available in a given programming language. While R library support for KEGG is fairly strong, Python library support has been lacking. Moreover, there …

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Bilirubin Nanoparticle Treatment In Obese Mice Inhibits Hepatic Ceramide Production And Remodels Liver Fat Content, Zachary A. Kipp, Genesee J. Martinez, Evelyn A. Bates, Agil B. Maharramov, Robert M. Flight, Hunter N. B. Moseley, Andrew J. Morris, David E. Stec, Terry D. Hinds Jr. Feb 2023

Bilirubin Nanoparticle Treatment In Obese Mice Inhibits Hepatic Ceramide Production And Remodels Liver Fat Content, Zachary A. Kipp, Genesee J. Martinez, Evelyn A. Bates, Agil B. Maharramov, Robert M. Flight, Hunter N. B. Moseley, Andrew J. Morris, David E. Stec, Terry D. Hinds Jr.

Markey Cancer Center Faculty Publications

Studies have indicated that increasing plasma bilirubin levels might be useful for preventing and treating hepatic lipid accumulation that occurs with metabolic diseases such as obesity and diabetes. We have previously demonstrated that mice with hyperbilirubinemia had significantly less lipid accumulation in a diet-induced non-alcoholic fatty liver disease (NAFLD) model. However, bilirubin’s effects on individual lipid species are currently unknown. Therefore, we used liquid chromatography-mass spectroscopy (LC-MS) to determine the hepatic lipid composition of obese mice with NAFLD treated with bilirubin nanoparticles or vehicle control. We placed the mice on a high-fat diet (HFD) for 24 weeks and then treated …

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Clic And Membrane Wound Repair Pathways Enable Pandemic Norovirus Entry And Infection, B. Vijayalakshmi Ayyar, Khalil Ettayebi, Wilhelm Salmen, Umesh C. Karandikar, Frederick H. Neill, Victoria R. Tenge, Sue E. Crawford, Erhard Bieberich, B. V. Venkataram Prasad, Robert L. Atmar, Mary K. Estes Feb 2023

Clic And Membrane Wound Repair Pathways Enable Pandemic Norovirus Entry And Infection, B. Vijayalakshmi Ayyar, Khalil Ettayebi, Wilhelm Salmen, Umesh C. Karandikar, Frederick H. Neill, Victoria R. Tenge, Sue E. Crawford, Erhard Bieberich, B. V. Venkataram Prasad, Robert L. Atmar, Mary K. Estes

Markey Cancer Center Faculty Publications

Globally, most cases of gastroenteritis are caused by pandemic GII.4 human norovirus (HuNoV) strains with no approved therapies or vaccines available. The cellular pathways that these strains exploit for cell entry and internalization are unknown. Here, using nontransformed human jejunal enteroids (HIEs) that recapitulate the physiology of the gastrointestinal tract, we show that infectious GII.4 virions and virus-like particles are endocytosed using a unique combination of endosomal acidification-dependent clathrin-independent carriers (CLIC), acid sphingomyelinase (ASM)-mediated lysosomal exocytosis, and membrane wound repair pathways. We found that besides the known interaction of the viral capsid Protruding (P) domain with host glycans, the Shell …

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Critical Role Of The Sulfiredoxin-Peroxiredoxin Iv Axis In Urethane-Induced Non-Small Cell Lung Cancer, Yanning Hao, Hong Jiang, Pratik Thapa, Na Ding, Aziza Alshahrani, Junichi Fujii, Michel B. Toledano, Qiou Wei Feb 2023

Critical Role Of The Sulfiredoxin-Peroxiredoxin Iv Axis In Urethane-Induced Non-Small Cell Lung Cancer, Yanning Hao, Hong Jiang, Pratik Thapa, Na Ding, Aziza Alshahrani, Junichi Fujii, Michel B. Toledano, Qiou Wei

Markey Cancer Center Faculty Publications

Non-small cell lung cancer (NSCLC), the most common type of lung cancer, etiologically associates with tobacco smoking which mechanistically contributes to oxidative stress to facilitate the occurrence of mutations, oncogenic transformation and aberrantly activated signaling pathways. Our previous reports suggested an essential role of Sulfiredoxin (Srx) in promoting the development of lung cancer in humans, and was causally related to Peroxiredoxin IV (Prx4), the major downstream substrate and mediator of Srx-enhanced signaling. To further explore the role of the Srx-Prx4 axis in de novo lung tumorigenesis, we established Prx4−/− and Srx−/−/Prx4−/− mice in pure FVB/N background. Together with wild-type litter …

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Metabolic Reprogramming Driven By Ezh2 Inhibition Depends On Cell–Matrix Interactions, Teresa W-M Fan, Jahid M. M. Islam, Richard M. Higashi, Penghui Lin, Christine F. Brainson, Andrew N. Lane Jan 2023

Metabolic Reprogramming Driven By Ezh2 Inhibition Depends On Cell–Matrix Interactions, Teresa W-M Fan, Jahid M. M. Islam, Richard M. Higashi, Penghui Lin, Christine F. Brainson, Andrew N. Lane

Markey Cancer Center Faculty Publications

EZH2 (Enhancer of Zeste Homolog 2), a subunit of Poly- comb Repressive Complex 2 (PRC2), catalyzes the trimethyla- tion of histone H3 at lysine 27 (H3K27me3), which represses expression of genes. It also has PRC2-independent functions, including transcriptional coactivation of oncogenes, and is frequently overexpressed in lung cancers. Clinically, EZH2 in- hibition can be achieved with the FDA-approved drug EPZ- 6438 (tazemetostat). To realize the full potential of EZH2 blockade, it is critical to understand how cell-cell/cell-matrix interactions present in 3D tissue and cell culture systems in- fluences this blockade in terms of growth-related metabolic functions. Here, we show that …

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A Monoadduct Generating Ru(Ii) Complex Induces Ribosome Biogenesis Stress And Is A Molecular Mimic Of Phenanthriplatin, Richard Joseph Mitchell, Sarah M. Kriger, Alexander D. Fenton, Dmytro Havrylyuk, Ankit Pandeya, Yang Sun, Tami Smith, Jason E. Derouchey, David K. Heidary, Edith C. Glazer Jan 2023

A Monoadduct Generating Ru(Ii) Complex Induces Ribosome Biogenesis Stress And Is A Molecular Mimic Of Phenanthriplatin, Richard Joseph Mitchell, Sarah M. Kriger, Alexander D. Fenton, Dmytro Havrylyuk, Ankit Pandeya, Yang Sun, Tami Smith, Jason E. Derouchey, David K. Heidary, Edith C. Glazer

Markey Cancer Center Faculty Publications

Ruthenium complexes are often investigated as potential replacements for platinum-based chemotherapeutics in hopes of identifying systems with improved tolerability in vivo and reduced susceptibility to cellular resistance mechanisms. Inspired by phenanthriplatin, a non-traditional platinum agent that contains only one labile ligand, monofunctional ruthenium polypyridyl agents have been developed, but until now, few demonstrated promising anticancer activity. Here we introduce a potent new scaffold, based on [Ru(tpy)(dip)Cl]Cl (tpy = 2,20:60,200-terpyridine and dip = 4,7-diphenyl-1,10-phenanthroline) in pursuit of effective Ru(II )-based monofunctional agents. Notably, the extension of the terpyridine at the 40 position with an aromatic ring resulted in a molecule that …

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Bilirubin Levels Are Negatively Correlated With Adiposity In Obese Men And Women, And Its Catabolized Product, Urobilin, Is Positively Associated With Insulin Resistance, Zachary A. Kipp, Mei Xu, Evelyn A. Bates, Wang-Hsin Lee, Philip A. Kern, Terry D. Hinds Jr. Jan 2023

Bilirubin Levels Are Negatively Correlated With Adiposity In Obese Men And Women, And Its Catabolized Product, Urobilin, Is Positively Associated With Insulin Resistance, Zachary A. Kipp, Mei Xu, Evelyn A. Bates, Wang-Hsin Lee, Philip A. Kern, Terry D. Hinds Jr.

Markey Cancer Center Faculty Publications

Bilirubin levels in obese humans and rodents have been shown to be lower than in their lean counterparts. Some studies have proposed that the glucuronyl UGT1A1 enzyme that clears bilirubin from the blood increases in the liver with obesity. UGT1A1 clearance of bilirubin allows more conjugated bilirubin to enter the intestine, where it is catabolized into urobilin, which can be then absorbed via the hepatic portal vein. We hypothesized that when bilirubin levels are decreased, the urobilin increases in the plasma of obese humans, as compared to lean humans. To test this, we measured plasma levels of bilirubin and urobilin, …

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Dysregulated Polycomb Repressive Complex 2 Contributes To Chronic Obstructive Pulmonary Disease By Rewiring Stem Cell Fate, Aria Byrd, Xufeng Qu, Alexsandr Lukyanchuk, Jinpeng Liu, Fan Chen, Kassandra J. Naughton, Tanner Ducote, Xiulong Song, Hannah Bowman, Yanming Zhao, Abigail R Edgin, Chi Wang, Jinze Liu, Christine Fillmore Brainson Jan 2023

Dysregulated Polycomb Repressive Complex 2 Contributes To Chronic Obstructive Pulmonary Disease By Rewiring Stem Cell Fate, Aria Byrd, Xufeng Qu, Alexsandr Lukyanchuk, Jinpeng Liu, Fan Chen, Kassandra J. Naughton, Tanner Ducote, Xiulong Song, Hannah Bowman, Yanming Zhao, Abigail R Edgin, Chi Wang, Jinze Liu, Christine Fillmore Brainson

Markey Cancer Center Faculty Publications

Aberrant lung cell differentiation is a hallmark of many lung diseases including chronic obstructive pulmonary disease (COPD). The EZH2-containing Polycomb Repressive Complex 2 (PRC2) regulates embryonic lung stem cell fate, but its role in adult lung is obscure. Histological analysis of patient tissues revealed that loss of PRC2 activity was correlated with aberrant bronchiolar cell differentiation in COPD lung. Histological and single-cell RNA-sequencing analyses showed that loss of EZH2 in mouse lung organoids led to lowered self- renewal capability, increased squamous morphological development, and marked shifts in progenitor cell populations. Evaluation of in vivo models revealed that heterozygosity of Ezh2 …

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Polycomb Deficiency Drives A Foxp2-High Aggressive State Targetable By Epigenetic Inhibitors, Fan Chen, Aria Byrd, Jinpeng Liu, Robert M. Flight, Tanner Ducote, Kassandra J. Naughton, Xiulong Song, Abigail R Edgin, Alexsandr Lukyanchuk, Danielle T. Dixon, Christian M. Gosser, Dave-Preston Esoe, Rani Jayswal, Stuart H. Orkin, Hunter N. B. Moseley, Chi Wang, Christine Fillmore Brainson Jan 2023

Polycomb Deficiency Drives A Foxp2-High Aggressive State Targetable By Epigenetic Inhibitors, Fan Chen, Aria Byrd, Jinpeng Liu, Robert M. Flight, Tanner Ducote, Kassandra J. Naughton, Xiulong Song, Abigail R Edgin, Alexsandr Lukyanchuk, Danielle T. Dixon, Christian M. Gosser, Dave-Preston Esoe, Rani Jayswal, Stuart H. Orkin, Hunter N. B. Moseley, Chi Wang, Christine Fillmore Brainson

Markey Cancer Center Faculty Publications

Inhibitors of the Polycomb Repressive Complex 2 (PRC2) histone methyltransferase EZH2 are approved for certain cancers, but realizing their wider utility relies upon understanding PRC2 biology in each cancer system. Using a genetic model to delete Ezh2 in KRAS-driven lung adenocarcinomas, we observed that Ezh2 haplo-insufficient tumors were less lethal and lower grade than Ezh2 fully-insufficient tumors, which were poorly differentiated and metastatic. Using three-dimensional cultures and in vivo experiments, we determined that EZH2-deficient tumors were vulnerable to H3K27 demethylase or BET inhibitors. PRC2 loss/inhibition led to de-repression of FOXP2, a transcription factor that promotes migration and stemness, and FOXP2 …

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Suppressing Hepatic Ugt1a1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways And Lipid Species And Improves Fatty Liver Disease, Evelyn A. Bates, Zachary A. Kipp, Genesee J. Martinez, Olufunto O. Badmus, Mangala M. Soundarapandian, Donald Foster, Mei Xu, Justin F. Creeden, Jennifer R. Greer, Andrew J. Morris, David E. Stec, Terry D. Hinds Jr. Jan 2023

Suppressing Hepatic Ugt1a1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways And Lipid Species And Improves Fatty Liver Disease, Evelyn A. Bates, Zachary A. Kipp, Genesee J. Martinez, Olufunto O. Badmus, Mangala M. Soundarapandian, Donald Foster, Mei Xu, Justin F. Creeden, Jennifer R. Greer, Andrew J. Morris, David E. Stec, Terry D. Hinds Jr.

Markey Cancer Center Faculty Publications

Several population studies have observed lower serum bilirubin levels in patients with non-alcoholic fatty liver disease (NAFLD). Yet, treatments to target this metabolic phenotype have not been explored. Therefore, we designed an N-Acetylgalactosamine (GalNAc) labeled RNAi to target the enzyme that clears bilirubin from the blood, the UGT1A1 glucuronyl enzyme (GNUR). In this study, male C57BL/6J mice were fed a high-fat diet (HFD, 60%) for 30 weeks to induce NAFLD and were treated subcutaneously with GNUR or sham (CTRL) once weekly for six weeks while continuing the HFD. The results show that GNUR treatments significantly raised plasma bilirubin levels and …

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The Link Between Intracellular Calcium Signaling And Exosomal Pd-L1 In Cancer Progression And Immunotherapy, Rakibul Alam, Mizanur Rahman, Zhiguo Li Jan 2023

The Link Between Intracellular Calcium Signaling And Exosomal Pd-L1 In Cancer Progression And Immunotherapy, Rakibul Alam, Mizanur Rahman, Zhiguo Li

Markey Cancer Center Faculty Publications

Exosomes are small membrane vesicles containing microRNA, RNA, DNA fragments, and proteins that are transferred from donor cells to recipient cells. Tumor cells release exo- somes to reprogram the factors associated with the tumor microenvironment (TME) causing tu- mor metastasis and immune escape. Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1 (PD-L1) that binds with re- ceptor program death protein 1 (PD-1) and promote tumor progression by escaping immune response. Currently, some FDA-approved monoclonal antibodies are clinically used for cancer treatment by blocking PD-1/PD-L1 interaction. Despite notable treatment outcomes, some pa- tients show …

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Cell-Intrinsic Melanin Fails To Protect Melanocytes From Ultraviolet-Mutagenesis In The Absence Of Epidermal Melanin, Tirzah J. Weiss, Emma R. Crawford, Valentina Posada, Hafeez Rahman, Tong Liu, Brandon M. Murphy, Tiffany E. Arnold, Shannon Gray, Zhexuan Hu, Rebecca C. Hennessey, Lianbo Yu, John August D'Orazio, Craig J. Burd, Jonathan H. Zippin, Douglas Grossman, Christin E. Burd Sep 2022

Cell-Intrinsic Melanin Fails To Protect Melanocytes From Ultraviolet-Mutagenesis In The Absence Of Epidermal Melanin, Tirzah J. Weiss, Emma R. Crawford, Valentina Posada, Hafeez Rahman, Tong Liu, Brandon M. Murphy, Tiffany E. Arnold, Shannon Gray, Zhexuan Hu, Rebecca C. Hennessey, Lianbo Yu, John August D'Orazio, Craig J. Burd, Jonathan H. Zippin, Douglas Grossman, Christin E. Burd

Markey Cancer Center Faculty Publications

Melanin is a free-radical scavenger, antioxidant, and broadband absorber of ultraviolet (UV) radiation which protects the skin from environmental carcinogenesis. However, melanin synthesis and UV-induced reactive melanin species are also implicated in melanocyte genotoxicity. Here, we attempted to reconcile these disparate functions of melanin using a UVB- sensitive, NRAS-mutant mouse model, TpN. We crossed TpN mice heterozygous for an inactivating mutation in Tyrosinase to produce albino and black littermates on a C57BL/6J background. These animals were then exposed to a single UVB dose on postnatal day three when keratinocytes in the skin have yet to be melanized. Approximately one-third (35%) …

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