A5081175392- Prostate Cancer Treatment and Research
- Cancer, Lipids, and Metabolism
- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Cancer Genomics and Diagnostics
- Epigenetics and DNA Methylation
- RNA Research and Splicing
- Protein Degradation and Inhibitors
- Immune Cell Function and Interaction
- interferon and immune responses
- Metabolomics and Mass Spectrometry Studies
- FOXO transcription factor regulation
- Adipokines, Inflammation, and Metabolic Diseases
- RNA modifications and cancer
- Immune cells in cancer
- Sarcoma Diagnosis and Treatment
University of Pennsylvania
2019-2025
California University of Pennsylvania
2021-2024
Metastatic castration-resistant prostate cancer (CRPC) is a fatal disease, primarily resulting from the transcriptional addiction driven by androgen receptor (AR). First-line CRPC treatments typically target AR signaling, but are rapidly bypassed, in only modest survival benefit with antiandrogens. Therapeutic approaches that more effectively block AR-transcriptional axis urgently needed. Here, we investigated molecular mechanism underlying association between coactivator MED1 and as...
Activated macrophages must carefully calibrate their inflammatory responses to balance efficient pathogen control with inflammation-mediated tissue damage, but the molecular underpinnings of this "balancing act" remain unclear. Using genetically engineered mouse models and primary macrophage cultures, we show that Toll-like receptor (TLR) signaling induces expression transcription factor Spic selectively in patrolling monocytes by a nuclear κB (NF-κB)-dependent mechanism. Functionally,...
Abstract Loss of the tumor suppressive activity protein phosphatase 2A (PP2A) is associated with cancer, but underlying molecular mechanisms are unclear. PP2A holoenzyme comprises a heterodimeric core, scaffolding A subunit and catalytic C subunit, one over 20 distinct substrate-directing regulatory B subunits. Methylation regulates heterotrimerization, affecting binding substrate specificity. Here, we report that leucine carboxy methyltransferase (LCMT1), which methylates L309 residue acts...
Abstract Changes in the methylation of proteins, nucleic acids, and metabolites are fundamental cancer development. Specifically, when these changes affect histones they can alter epigenetic status cells, impacting expression thousands genes driving initiation progression. S-adenosylmethionine (SAM) is universal methyl donor for SAM-dependent reactions, while its byproduct, S-adenosylhomocysteine (SAH), inhibits methyltransferases, including HMTase DNMTs. Dysregulation SAM, SAH, their ratio...
Abstract Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer for which development of effective therapies urgently needed. Metabolic programs are vastly remodeled in pancreatic to favor the production certain metabolites that support tumor progression. Previous studies reported catabolism branched-chain amino acids (BCAAs) major carbon source energy healthy acinar cells. However, PDA cells, BCAA metabolism reprogrammed and its contribution TCA cycle suppressed. Our labs recently showed...
Ewing sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children adolescents. The pathognomonic oncofusion EWSR1::FLI1 transcription factor drives EwS by orchestrating an oncogenic program through de novo enhancers. By integrative analysis thousands transcriptomes representing pan-cancer cell lines, primary cancers, metastasis, normal tissues, we identify 32-gene signature (ESS32 [Ewing Sarcoma Specific 32]) stratifies from pan-cancer. Among the ESS32,...
The androgen receptor (AR) is a ligand-responsive transcription factor that binds at enhancers to drive terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy extensively reprogrammed hyper-proliferative, metastatic, or therapy-resistant phenotypes, molecular mechanisms which remain poorly understood. Here, we show tumor-specific enhancer circuitry critically reliant on activity Nuclear Receptor Binding SET...
Branched-chain amino acid (BCAA) catabolism contributes prominently to the TCA cycle in healthy pancreas but is suppressed pancreatic ductal adenocarcinoma (PDA). The impact of this metabolic remodeling on cancer phenotypes remains poorly understood. Here, we find that BCAA isoleucine a primary source propionyl-CoA PDA cells. Reduction availability by either genetic perturbation or and valine starvation decreases histone propionylation (Kpr) without impacting acetylation specific lysine...
<p>Supplementary Figures S1-S12, Supplementary Table S1-3, supplementary methods and reference.</p>
<div>Abstract<p>Metastatic castration-resistant prostate cancer (CRPC) is a fatal disease, primarily resulting from the transcriptional addiction driven by androgen receptor (AR). First-line CRPC treatments typically target AR signaling, but are rapidly bypassed, in only modest survival benefit with antiandrogens. Therapeutic approaches that more effectively block AR-transcriptional axis urgently needed. Here, we investigated molecular mechanism underlying association between...
<p>Supplementary Figures S1-S12, Supplementary Table S1-3, supplementary methods and reference.</p>
Abstract The androgen receptor (AR) is a ligand-responsive transcription factor (TF) that binds as homodimer at FOXA1-pioneered enhancer elements containing palindromic DNA motif. Prostate cancer (PCa) highly dependent on the AR enhanceosome complex, and in castration-resistant disease, this dependency reinforced through alterations pathway. This centrally involves extensive rewiring of cistrome to gain de novo binding sites (aka neo-enhancers) activate hyperproliferative metastatic gene...
<div>Abstract<p>Metastatic castration-resistant prostate cancer (CRPC) is a fatal disease, primarily resulting from the transcriptional addiction driven by androgen receptor (AR). First-line CRPC treatments typically target AR signaling, but are rapidly bypassed, in only modest survival benefit with antiandrogens. Therapeutic approaches that more effectively block AR-transcriptional axis urgently needed. Here, we investigated molecular mechanism underlying association between...
Ewing Sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children adolescents. The pathognomonic oncofusion EWSR1-ETS (EWSR1-FLI1/EWSR1-ERG) transcription factors drive EwS by orchestrating an oncogenic program through de novo enhancers. Pharmacological targeting these oncofusions has been challenged unstructured prion-like domains common DNA binding in the EWSR1 ETS protein, respectively. Alternatively, identification characterization mediators...