A5086832556- Polyamine Metabolism and Applications
- Cannabis and Cannabinoid Research
- Cancer, Hypoxia, and Metabolism
- Epigenetics and DNA Methylation
- Cancer, Lipids, and Metabolism
- Amino Acid Enzymes and Metabolism
- Pancreatic and Hepatic Oncology Research
- RNA modifications and cancer
- Immune cells in cancer
- Prostate Cancer Treatment and Research
- Pancreatic function and diabetes
- Dietary Effects on Health
- Cancer Research and Treatments
- Diet and metabolism studies
- Ferroptosis and cancer prognosis
- Metabolism and Genetic Disorders
- FOXO transcription factor regulation
- Cancer-related gene regulation
- Acute Lymphoblastic Leukemia research
- Endoplasmic Reticulum Stress and Disease
- Advanced Proteomics Techniques and Applications
- Diet, Metabolism, and Disease
- Cancer therapeutics and mechanisms
- Mitochondrial Function and Pathology
- RNA and protein synthesis mechanisms
University of Pennsylvania
2018-2025
Cancer Research Institute
2019-2025
UPMC Hillman Cancer Center
2019-2025
Roswell Park Comprehensive Cancer Center
2013-2023
Cancer Genetics (United States)
2015-2021
Siena College
2020
Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring
Understanding metabolic dysregulation in different disease settings is vital for the safe and effective incorporation of metabolism-targeted therapeutics clinic. Here, using transcriptomic data 10,704 tumor normal samples from The Cancer Genome Atlas, across 26 sites, we present a novel bioinformatics pipeline that distinguishes tissues, based on differential gene expression 114 pathways. We confirm pathway separate patient populations, demonstrating robustness our approach. Bootstrapping...
Macrophages use mitochondrial lactate metabolism for ACLY-dependent histone acetylation, immune suppression, and tumor progression.
The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation nucleus. two canonical precursors to nuclear-cytoplasmic compartment are citrate acetate, which processed by ATP-citrate lyase (ACLY) acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It unclear whether other substantial routes nuclear-cytosolic exist. To investigate this, we generated cancer cell lines lacking ACLY ACSS2 [double knockout (DKO) cells]. Using stable isotope tracing,...
Diet and healthy weight are established means of reducing cancer incidence mortality. However, the impact diet modifications on tumor microenvironment antitumor immunity is not well defined. Immunosuppressive tumor-associated macrophages (TAMs) associated with poor clinical outcomes potentially modifiable through dietary interventions. We tested hypothesis that protein restriction modifies macrophage function toward phenotypes.Macrophage functional status under different tissue culture...
Sugars and refined carbohydrates are major components of the modern diet. ATP-citrate lyase (ACLY) is upregulated in adipocytes response to carbohydrate consumption generates acetyl-coenzyme A (CoA) for both lipid synthesis acetylation reactions. Here, we investigate role ACLY metabolic transcriptional responses unexpectedly uncover a sexually dimorphic function maintaining systemic homeostasis. When fed high-sucrose diet, AclyFAT−/− females exhibit lipodystrophy-like phenotype, with minimal...
Abstract Prostatic luminal epithelial cells secrete high levels of acetylated polyamines into the prostatic lumen, sensitizing them to perturbations connected metabolic pathways. Enhanced flux is driven by spermidine/spermine N1-acetyltransferase (SSAT) activity, which acetylates leading their secretion and drives biosynthetic demand. The methionine salvage pathway recycles one-carbon units lost polyamine biosynthesis cycle overcome stress. Prostate cancer (CaP) relies on methylthioadenosine...
Tumors frequently exhibit aberrant glycosylation, which can impact cancer progression and therapeutic responses. The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a major substrate for glycosylation in the cell. Prior studies have identified HBP as promising target pancreatic ductal adenocarcinoma (PDA). requires both glucose glutamine its initiation. PDA tumor microenvironment is nutrient poor, however, prompting us to investigate how...
Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is central transcriptional regulator of xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct activation 2 genes, ODC1 and AZIN1, which are involved biosynthesis control, respectively. In patients with multiple myeloma (MM), levels were inversely correlated...
Metabolic and epigenetic reprogramming are characteristics of cancer cells that, in many cases, linked. Oncogenic signaling, diet, tumor microenvironment each influence the availability metabolites that substrates or inhibitors enzymes. Reciprocally, altered expression activity chromatin-modifying enzymes can exert direct indirect effects on cellular metabolism. In this article, we discuss bidirectional relationship between epigenetics metabolism cancer. First, focus control metabolism,...
This study addresses the roles of nuclear receptor corepressor 2 (NCOR2) in prostate cancer (PC) progression response to androgen deprivation therapy (ADT). Reduced NCOR2 expression significantly associates with shorter disease-free survival patients PC receiving adjuvant ADT. Utilizing CWR22 xenograft model, we demonstrate that stably reduced accelerates disease recurrence following ADT, gene patterns include neuroendocrine features, and induces DNA hypermethylation. Stably isogenic LNCaP...
Prostatic epithelial cells secrete high levels of acetylated polyamines into the prostatic lumen. This distinctive characteristic places added strain on connected pathways, which are forced to increase metabolite production maintain pools. The methionine salvage pathway recycles one-carbon unit lost polyamine biosynthesis back cycle, allowing for replenishment SAM pools providing a mechanism help mitigate metabolic stress associated with flux through these pathways. rate-limiting enzyme...
ATP-citrate lyase (ACLY) generates cytosolic acetyl-coenzyme A (acetyl-CoA) for lipid synthesis and is a promising therapeutic target in diseases with altered metabolism. Here, we developed inducible whole-body Acly-knockout mice to determine the requirement ACLY normal tissue functions, uncovering its crucial role skin homeostasis. ACLY-deficient upregulates acetyl-CoA synthetase ACSS2; deletion of both Acly Acss2 from exacerbates abnormalities, differential effects on two major...
ATP-citrate lyase (ACLY) links carbohydrate and lipid metabolism provides nucleocytosolic acetyl-CoA necessary for protein acetylation. ACLY has two major splice isoforms: the full-length canonical "long" isoform an uncharacterized "short" in which exon 14 is spliced out. Exon encodes 10 amino acids within a disordered region of includes at least 1 site that dynamically phosphorylated. Both isoforms are expressed healthy tissues to varying degrees. Analysis human transcriptomic data revealed...
// Hayley C. Affronti 1 , Mark D. Long Spencer R. Rosario Bryan M. Gillard 2 Ellen Karasik Christoph S. Boerlin Anthony J. Pellerite Barbara A. Foster Kristopher Attwood 3 Roberto Pili 4 John H. Wilton Moray Campbell 5 and Dominic Smiraglia Department of Cancer Genetics, Roswell Park Institute, Buffalo, NY, USA Pharmacology Therapeutics, Biostatistics, Hematology Oncology, Indiana University, Indianapolis, IN, College Pharmacy, Pharmaceutics Pharmaceutical Chemistry, The Ohio State Columbus,...
Background CWR22 is a human xenograft model of primary prostate cancer (PCa) that often utilized to study castration recurrent (CR) PCa. recapitulates clinical response androgen deprivation therapy (ADT), in tumors regress castration, but can recur after period time. Methods Two cohorts mice, totaling 117 mice were implanted with CWR22, allowed develop tumors, castrated by pellet removal and followed for 32 50 weeks. Mice presenting >2.0 cm3 at the site, moribund appearance, or palpable...
ABSTRACT Acetyl-CoA is a central metabolite used for lipid synthesis in the cytosol and histone acetylation nucleus, among other pathways. The two major precursors to acetyl-CoA nuclear-cytoplasmic compartment are citrate acetate, which processed by ATP-citrate lyase (ACLY) acyl-CoA synthetase short-chain 2 (ACSS2), respectively. While some evidence has suggested existence of additional routes nuclear-cytosolic acetyl-CoA, such pathways remain poorly defined. To investigate this, we...
Understanding the epigenetic control of normal differentiation programs might yield principal information about critical regulatory states that are disturbed in cancer. We utilized established non-malignant HPr1-AR prostate epithelial cell model upon androgen exposure commits to a luminal trajectory from basal-like state. profile dynamic transcriptome associated with this transition at multiple time points (0 h, 1 24 96 h), and confirm expression patterns strongly indicative progressive...
Abstract Identifying and leveraging unique points of metabolic dysregulation in different disease settings is vital for safe effective incorporation metabolism-targeted therapies the clinic. In addition, it has been shown identification master transcriptional regulators (MMTR) individual pathways, how they relate to question, may offer key understanding therapeutic response. prostate cancer, we have previously demonstrated polyamine biosynthesis methionine cycle were targetable...
Abstract T-cell Acute Lymphoblastic Leukemia (T-ALL) is a hematological malignancy in need of novel therapeutic approaches. Here, we identify the ATP-citrate lyase ACLY as overexpressed and target T-ALL. To test effects leukemia progression, developed an isogenic model NOTCH1-induced Acly conditional knockout leukemia. Importantly, observed intrinsic antileukemic upon loss ACLY, which further synergized with NOTCH1 inhibition vivo. Metabolomic profiling revealed metabolic crisis reduced...