Siyuan Chang, Jing Huang, Huan Niu, Jing Wang, Yang Si, Zhigang Bai, Shan Cheng, Wei Ding
Background: Drug resistance to 5-fluorouracil (5-FU) and recurrence after chemotherapy in colorectal cancer remain a challenge to be resolved for the improvement of patient outcomes. It is recognized that a variety of secretory proteins released from the tumor cells exposed to chemo-drugs into the tumor microenvironment (TME) contributed to the cell-to-cell communication, and altered the drug sensitivity. One of these important factors is osteopontin (OPN), which exists in several functional forms from alternative splicing and post-translational processing...
2020: Cancer Cell International
Hee Chan Yoo, Ya Chun Yu, Yulseung Sung, Jung Min Han
As knowledge of cell metabolism has advanced, glutamine has been considered an important amino acid that supplies carbon and nitrogen to fuel biosynthesis. A recent study provided a new perspective on mitochondrial glutamine metabolism, offering mechanistic insights into metabolic adaptation during tumor hypoxia, the emergence of drug resistance, and glutaminolysis-induced metabolic reprogramming and presenting metabolic strategies to target glutamine metabolism in cancer cells. In this review, we introduce the various biosynthetic and bioenergetic roles of glutamine based on the compartmentalization of glutamine metabolism to explain why cells exhibit metabolic reliance on glutamine...
September 17, 2020: Experimental & Molecular Medicine
Robert J Norgard, Ben Z Stanger
Metastasis and chemoresistance, the most lethal features of cancer progression, are strongly associated with a form of cellular plasticity known as the epithelial-to-mesenchymal transition (EMT). Carcinoma cells undergoing EMT lose their epithelial morphology and become more mobile, allowing them to invade and migrate more efficiently. This shift is also associated with a change in vulnerability to chemotherapeutic agents. Importantly, EMT does not involve a single mechanism, but rather encompasses a spectrum of phenotypes with differing degrees of epithelial and mesenchymal characteristics...
2021: Methods in Molecular Biology
Pavan Bachireddy, Christina Ennis, Vinhkhang N Nguyen, Satyen H Gohil, Kendell Clement, Sachet A Shukla, Juliet Forman, Nikolaos Barkas, Samuel Freeman, Natalie Bavli, Liudmila Elagina, Ignaty Leshchiner, Arman W Mohammad, Nathan D Mathewson, Derin B Keskin, Laura Z Rassenti, Thomas J Kipps, Jennifer R Brown, Gad Getz, Vincent T Ho, Andreas Gnirke, Donna Neuberg, Robert J Soiffer, Jerome Ritz, Edwin P Alyea, Peter V Kharchenko, Catherine J Wu
Leukemic relapse remains a major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis for relapse of advanced lymphoid malignancies remains incompletely understood and may involve escape from the graft-versus-leukemia (GvL) effect. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell-intrinsic features influence transplant outcomes by directing the evolutionary trajectories of CLL cells...
September 16, 2020: Science Translational Medicine
Yuxin Li, Yao Liu, Na Zhao, Xiaojun Yang, Yaqing Li, Fangzheng Zhai, Xingxing Zang, Wei Cui
HDAC inhibitors are efficacious for treating lymphoma, but display limited efficacy in treating solid tumors. Here, we investigated the relationship between HDAC inhibitor resistance and the tumor immune environment in colorectal cancer. Our data indicated that among the investigated immune factors, B7x expression was enhanced in HDAC inhibitor-resistant colorectal cancer models in vitro and in vivo. In addition, gene manipulation results demonstrated that xenograft mice with tumors derived from a B7x-overexpressing CT-26 colorectal cancer cell line were resistant to HDAC inhibitor treatment...
September 15, 2020: Cell Death & Disease
Mi Ran Kim, Meng-Ju Wu, Yingsheng Zhang, Jer-Yen Yang, Chun Ju Chang
Epigenetic regulation plays an important role in governing stem cell fate and tumorigenesis. Lost expression of a key DNA demethylation enzyme TET2 is associated with human cancers and has been linked to stem cell traits in vitro; however, whether and how TET2 regulates mammary stem cell fate and mammary tumorigenesis in vivo remains to be determined. Here, using our recently established mammary specific Tet2 deletion mouse model, the data reveals that TET2 plays a pivotal role in mammary gland development and luminal lineage commitment...
September 15, 2020: Nature Communications
Phillip Thienger, Mark A Rubin
An outgrowth of therapy-resistant prostate cancers (PCa) with enhanced metastatic potential may be triggered by inhibitors of androgen receptor (AR) signaling, often via epigenetic rewiring. In this issue of Cancer Cell, Yuan et al. demonstrate how SETD2 integrates EZH2 and AMPK signaling pathways to keep PCa metastasis in check.
September 14, 2020: Cancer Cell
Junbao Zhang, Ying Ying, Meiqi Li, Maolin Wang, Xiaoyan Huang, Min Jia, Junhui Zeng, Canjie Ma, Yixiang Zhang, Chen Li, Xiaomei Wang, Xing-Sheng Shu
Tumor-initiating cells (TICs) maintain heterogeneity within tumors and seed metastases at distant sites, contributing to therapeutic resistance and disease recurrence. In colorectal cancer (CRC), strategy that effectively eradicates TICs and is of potential value for clinical use still remains in need. Methods : The anti-tumorigenic activity of a small-molecule inhibitor of KDM6 histone demethylases named GSK-J4 in CRC was evaluated by in vitro assays and in vivo imaging of xenografted tumors. Sphere formation, flow cytometry analysis of cell surface markers and intestinal organoid formation were performed to examine the impact of GSK-J4 on TIC properties...
2020: Theranostics
Eiji Sugihara, Norisato Hashimoto, Satoru Osuka, Takatsune Shimizu, Sayaka Ueno, Shogo Okazaki, Tomonori Yaguchi, Yutaka Kawakami, Kenjiro Kosaki, Taka-Aki Sato, Shinichiro Okamoto, Hideyuki Saya
Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation of Fas is required for both lymphoma development and lymphoma cell survival to evade immune cytotoxicity. CD40 signal activation significantly restored Fas expression and thereby induced apoptosis after Fas ligand treatment in both mouse and human lymphoma cells...
September 14, 2020: Cancer Research
Neeraj K Sharma, Mary E Comeau, Dennis Montoya, Matteo Pellegrini, Timothy D Howard, Carl D Langefeld, Swapan K Das
Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in Type 2 Diabetes. We hypothesize that differential DNA methylation (DNAm) controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating AT DNAm profiles with transcript profile data measured in a cohort of 230 African Americans from AAGMEx cohort, we performed cis -expression quantitative trait methylation ( cis -eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait-associated transcripts...
September 14, 2020: Diabetes
Sabrina Fritah, Arnaud Muller, Wei Jiang, Ramkrishna Mitra, Mohamad Sarmini, Monika Dieterle, Anna Golebiewska, Tao Ye, Eric Van Dyck, Christel Herold-Mende, Zhongming Zhao, Francisco Azuaje, Simone P Niclou
Resistance to chemotherapy by temozolomide (TMZ) is a major cause of glioblastoma (GBM) recurrence. So far, attempts to characterize factors that contribute to TMZ sensitivity have largely focused on protein-coding genes, and failed to provide effective therapeutic targets. Long noncoding RNAs (lncRNAs) are essential regulators of epigenetic-driven cell diversification, yet, their contribution to the transcriptional response to drugs is less understood. Here, we performed RNA-seq and small RNA-seq to provide a comprehensive map of transcriptome regulation upon TMZ in patient-derived GBM stem-like cells displaying different drug sensitivity...
September 10, 2020: Cancers
Chantelle L Ahlenstiel, Geoff Symonds, Stephen J Kent, Anthony D Kelleher
The HIV latent reservoir represents the major challenge to cure development. Residing in resting CD4+ T cells and myeloid cells at multiple locations in the body, including sanctuary sites such as the brain, the latent reservoir is not eliminated by ART and has the ability to reactivate virus replication to pre-therapy levels when ART is ceased. There are four broad areas of HIV cure research. The only successful cure strategy, thus far, is stem cell transplantation using naturally HIV resistant CCR5Δ32 stem cells...
2020: Frontiers in Cellular and Infection Microbiology
Miriam A Schiele, Christiane Thiel, Leonie Kollert, Lena Fürst, Lisa Putschin, Rebekka Kehle, Walter Hauke, Marina Mahr, Elena Reinhold, Michael G Gottschalk, Markus Heinrichs, Michael Zaudig, Götz Berberich, Katharina Domschke
INTRODUCTION: Obsessive-compulsive disorder (OCD) is associated with high chronicity and treatment resistance, indicating the need for early therapy response markers enabling fast and personalized treatment adaptations. Although epigenetic mechanisms such as DNA methylation of the oxytocin receptor (OXTR) gene have previously been linked to OCD pathogenesis, epigenetic markers as predictors of treatment success have not yet been investigated in OCD. OBJECTIVE: For the first time, this therapyepigenetic study aimed to investigate the role of OXTR methylation as a treatment response marker in OCD...
September 11, 2020: Psychotherapy and Psychosomatics
Chuntao Quan, Yuchen Chen, Xiaomu Wang, Dong Yang, Qing Wang, Yixue Huang, Robert B Petersen, Xinran Liu, Ling Zheng, Yangkai Li, Kun Huang
Tyrosine kinase inhibitor (TKI) treatment is the first-line therapy for non-small cell lung cancer (NSCLC) caused by activating mutations of epidermal growth factor receptor (EGFR). However, acquired resistance to EGFR-TKI occurs almost inevitably. Aberrant activation of proto-oncogene MET has been known to confer EGFR-TKI resistance; however, the mechanisms involved remains unclear. Recent evidence implicates epigenetic heterogeneity as playing roles in cancer drug resistance, whereas links involving epigenetic heterogeneity and MET in NSCLC remain poorly understood...
September 10, 2020: Cancer Letters
Xueling Lu, Eliza Fraszczyk, Thomas P van der Meer, Martijn van Faassen, Vincent W Bloks, Ido P Kema, André P van Beek, Shuang Li, Lude Franke, Harm-Jan Westra, Xijin Xu, Xia Huo, Harold Snieder, Bruce H R Wolffenbuttel, Jana V van Vliet-Ostaptchouk
BACKGROUND: Exposure to environmental endocrine disrupting chemicals (EDCs) may play an important role in the epidemic of metabolic diseases. Epigenetic alterations may functionally link EDCs with gene expression and metabolic traits. OBJECTIVES: We aimed to evaluate metabolic-related effects of the exposure to endocrine disruptors including five parabens, three bisphenols, and 13 metabolites of nine phthalates as measured in 24-hour urine on epigenome-wide DNA methylation...
September 8, 2020: Environment International
Yuting Wu, Yingshi Zhang, Xiaochun Qin, Haobin Geng, Daiying Zuo, Qingchun Zhao
Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide with high prevalence and lethality. The oncogenic phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is a classic dysregulated pathway involved in the pathogenesis of HCC. However, the underlying mechanism for how PI3K/AKT/mTOR pathway aberrantly activates HCC has not been entirely elucidated. The recognition of the functional roles of long non-coding RNAs (lncRNAs) in PI3K/AKT/mTOR signaling axis sheds light on a new dimension to our understanding of hepatocarcinogenesis...
September 8, 2020: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Shareen Singh, Thakur Gurjeet Singh, Ashish Kumar Rehni
Epilepsy is a second most common neurological disease with abnormal neural activity involving activation of various intracellular signalling transduction mechanisms. The molecular and system biology mechanisms responsible for epileptogenesis are not well defined or understood. Neuroinflammation, neurodegeneration & Epigenetic modification elicit epileptogensis. The excessive neuronal activities in brain are associated with neurochemical changes underlying the deleterious consequences of excitotoxicity. The prolonged repetitive excessive neuronal activities extended to brain tissue injury by activation of microglia regulating abnormal neuroglia remodelling and monocyte infiltration in response to brain lesions inducing axonal sprouting contributing to neurodegeneration...
September 10, 2020: CNS & Neurological Disorders Drug Targets
Sito Torres-Garcia, Imtiyaz Yaseen, Manu Shukla, Pauline N C B Audergon, Sharon A White, Alison L Pidoux, Robin C Allshire
Heterochromatin that depends on histone H3 lysine 9 methylation (H3K9me) renders embedded genes transcriptionally silent1-3 . In the fission yeast Schizosaccharomyces pombe, H3K9me heterochromatin can be transmitted through cell division provided the counteracting demethylase Epe1 is absent4,5 . Heterochromatin heritability might allow wild-type cells under certain conditions to acquire epimutations, which could influence phenotype through unstable gene silencing rather than DNA change6,7 . Here we show that heterochromatin-dependent epimutants resistant to caffeine arise in fission yeast grown with threshold levels of caffeine...
September 9, 2020: Nature
Daelynn R Buelow, Jason T Anderson, Stanley B Pounds, Lei Shi, Jatinder K Lamba, Shuiying Hu, Alice A Gibson, Emily A Goodwin, Alex Sparreboom, Sharyn D Baker
Reduced expression of the uptake transporter, OCTN1 (SLC22A4), has been reported as a strong predictor of poor event-free and overall survival in multiple cohorts of patients with acute myeloid leukemia (AML) receiving the cytidine nucleoside analog, cytarabine (Ara-C). To further understand the mechanistic basis of interindividual variability in the functional expression of OCTN1 in AML, we hypothesized a mechanistic connection to DNA methylation-based epigenetic repression of SLC22A4. We found increased basal SLC22A4 methylation was associated with decreased Ara-C uptake in AML cell lines...
September 9, 2020: Clinical and Translational Science
Fnu Sapna, Pal Satyajit Singh Athwal, Mukesh Kumar, Sandeep Randhawa, Sukhmanii Kahlon
Breast cancer is a frequently occurring malignancy in women. Immunologically, breast cancers can be classified into four subtypes depending on the types of receptors present and their expression profiles. These are estrogen positive, progesterone positive, human epidermal growth factor receptor type 2 (HER2) positive, and triple-negative as identified by immunohistochemistry. This classification is the basis of response to treatment, prognosis, and survival. With the identification of HER2 receptor overexpression, targeted therapies with anti-HER2 agents have been developed...
August 2, 2020: Curēus
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