Oligomerization of PRMT1 Regulated RNA-Binding Protein Cascade Promotes Pancreatic Ductal Adenocarcinoma DOI Open Access
Yi Ru, Xinyi Zhou,

Xijiao Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 11, 2024

Abstract PRMT1 is the predominant type I protein arginine methyltransferase responsible for generating monomethylarginine and asymmetric dimethylarginine (MMA ADMA) in various substrates. It regulates numerous biological processes, including RNA metabolism, mRNA splicing, DNA damage repair, chromatin dynamics. The crystal structure of rat has been previously reported as a homodimer; however, higher-order oligomeric species human have observed vivo, their structural basis remains elusive. In this study, we present cryo-EM its form, revealing novel interfaces crucial self-assembly normal function. shows strong preference intrinsically disordered RGG/RG motifs, which are commonly found RNA-binding proteins (RBPs), highlighting critical role regulating metabolism. vitro studies indicate that disrupting oligomerization impairs binding affinity RGG motif substrates, thereby reducing methylation levels on these This finding emphasizes essential state function with motif-containing RBPs. loss leads to decreased global ADMA pancreatic ductal adenocarcinoma (PDAC) cells inhibits PDAC tumor growth. Collectively, propose oligomerization, rather than mere dimerization, sufficient PRMT1-driven growth, offering insights into potential therapeutic targeting forms PDAC. Graphical abstract

Language: Английский

The roles of KRAS in cancer metabolism, tumor microenvironment and clinical therapy DOI Creative Commons

Qinglong Ma,

Wenyang Zhang, Kongming Wu

et al.

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 13, 2025

Abstract KRAS is one of the most mutated genes, driving alternations in metabolic pathways that include enhanced nutrient uptaking, increased glycolysis, elevated glutaminolysis, and heightened synthesis fatty acids nucleotides. However, beyond mechanisms KRAS-modulated cancer metabolisms remain incompletely understood. In this review, we aim to summarize current knowledge on KRAS-related alterations cells explore prevalence significance mutation shaping tumor microenvironment influencing epigenetic modification via various molecular activities. Given rely these changes sustain cell growth survival, targeting processes may represent a promising therapeutic strategy for KRAS-driven cancers.

Language: Английский

Citations

4
Towards the Targeted Protein Degradation of PRMT1 DOI Creative Commons

Poppy L. Martin,

F. Javier Pérez-Areales,

Shalini V. Rao

et al.

ChemMedChem, Journal Year: 2024, Volume and Issue: 19(16)

Published: May 10, 2024

Targeting the protein arginine methyltransferase 1 (PRMT1) has emerged as a promising therapeutic strategy in cancer treatment. The phase clinical trial for GSK3368715, first PRMT1 inhibitor to enter clinic, was terminated early due lack of efficacy, extensive treatment-emergent effects, and dose-limiting toxicities. incidence latter two events may be associated with inhibition-driven pharmacology high sustained concentration is required effect. degradation using proteolysis targeting chimera (PROTAC) superior inhibition proceeds via event-driven where PROTAC acts catalytically at low dose. PROTACs containing same pharmacophore combined motif that recruits VHL or CRBN E3-ligase, were synthesised. Suitable cell permeability target engagement shown selected candidates by detection downstream effects NanoBRET assay E3-ligase binding, however did not induce degradation. This paper reported investigation targeted provides hypotheses insights assist design other novel proteins.

Language: Английский

Citations

10
Pancreatic ductal adenocarcinoma cells reshape the immune microenvironment: Molecular mechanisms and therapeutic targets DOI Creative Commons
Yutong Zhao,

C.M. Qin,

Lin Chen

et al.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: 1879(6), P. 189183 - 189183

Published: Sept. 19, 2024

Language: Английский

Citations

4
Chromatin accessibility: biological functions, molecular mechanisms and therapeutic application DOI Creative Commons
Yang Chen, Rui Liang, Yong Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Dec. 4, 2024

Abstract The dynamic regulation of chromatin accessibility is one the prominent characteristics eukaryotic genome. inaccessible regions are mainly located in heterochromatin, which multilevel compressed and access restricted. remaining accessible loci generally euchromatin, have less nucleosome occupancy higher regulatory activity. opening most important prerequisite for DNA transcription, replication, damage repair, regulated by genetic, epigenetic, environmental, other factors, playing a vital role multiple biological progresses. Currently, based on susceptibility difference occupied or free to enzymatic cleavage, solubility, methylation, transposition, there many methods detect both bulk single-cell level. Through combining with high-throughput sequencing, genome-wide landscape tissues cells types also been constructed. feature distinct different states. Research network crucial uncovering secret various processes. In this review, we comprehensively introduced major functions mechanisms variation physiological pathological processes, meanwhile, targeted therapies dynamics summarized.

Language: Английский

Citations

4
Leveraging Epigenetic Alterations in Pancreatic Ductal Adenocarcinoma for Clinical Applications DOI Creative Commons
Jörg Tost,

Secil Ak-Aksoy,

Daniele Campa

et al.

Seminars in Cancer Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
PRMT1-Catalyzed NUSAP1 Methylation Enhances Notch2 Signaling and 5-FU Resistance in Gastric Cancer DOI Creative Commons

Feng Wang,

Steve Jiang,

Guoli Li

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Abstract 5-Fluorouracil (5-FU) resistance remains a significant challenge in the treatment of gastric cancer, limiting its clinical efficacy. Our study identifies NUSAP1, nucleolar and spindle-associated protein, as key driver 5-FU cancer. Proteomic analyses 5-FU-resistant cancer cell lines revealed that NUSAP1 is significantly upregulated, functional studies demonstrated essential role promoting resistance, proliferation, migration, invasion, tumor growth. Mechanistic investigations undergoes asymmetric dimethylation (ADMA) at R418 R422, mediated by PRMT1, with R422 site being critical for function. interacts PEST domain Notch2 through site, inhibiting ubiquitination stabilizing expression, thereby activating signaling pathway. This pathway closely linked to progression chemoresistance. Inhibition PRMT1 or mutation abrogated NUSAP1’s ability stabilize regulate downstream signaling. These findings unveil novel mechanism which promotes highlight therapeutic potential targeting NUSAP1-Notch2 axis overcoming

Language: Английский

Citations

0
Phenotypic heterogeneity and tumor immune microenvironment directed therapeutic strategies in pancreatic ductal adenocarcinoma DOI Creative Commons

R. Ramesh,

Hadida Yasmin, Pretty Ponnachan

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 31, 2025

Pancreatic cancer is an aggressive tumor with high metastatic potential which leads to decreased survival rate and resistance chemotherapy immunotherapy. Nearly 90% of pancreatic comprises ductal adenocarcinoma (PDAC). About 80% diagnoses takes place at the advanced stage when it unresectable, renders regimens ineffective. There also a dearth specific biomarkers for early-stage detection. Advances in next generation sequencing single cell profiling have identified molecular alterations signatures that play role PDAC progression subtype plasticity. Most shown only modest benefits, therefore, translational approaches immunotherapies combination therapies are urgently required. In this review, we examined immunosuppressive dense stromal network immune microenvironment various metabolic transcriptional changes underlie pro-tumorigenic properties terms phenotypic heterogeneity, plasticity co-existence. Moreover, heterogeneity as well genetic epigenetic impact development discussed. We review interaction sequestered cellular humoral components present modify outcome radiation therapy. Finally, discuss different therapeutic interventions targeting aimed better prognosis improved PDAC.

Language: Английский

Citations

0
The FOXP1-ABCG2 axis promotes the proliferation of cancer stem cells and induces chemoresistance in pancreatic cancer DOI Creative Commons

Woosol Chris Hong,

Minsoo Kim, Ju-Hyun Kim

et al.

Cancer Gene Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Abstract Pancreatic cancer is an aggressive disease with low survival and high recurrence rates. A major obstacle in treating pancreatic the frequent development of chemoresistance to standard therapeutic drug, gemcitabine. One mechanism by which develops through proliferation stem cells (CSC). However, mechanisms regulating stemness chemoresistant tumors remain unclear. Here, we found that expression transcription factor Forkhead Box P1 (FOXP1) was elevated crucial for establishing CSC characteristics. Silencing FOXP1 reduced expressions stemness-associated genes diminished formation both spheroids colonies, highlighting role tumor cells. Mechanistically, discovered regulates ATP-binding cassette superfamily G member 2 (ABCG2), induces efflux Knockdown ABCG2, resulting decreased increased sensitivity Moreover, inhibition orthotopic mouse models growth proliferation, enhanced Together, our data reveal as a potent oncogene promotes cancer.

Language: Английский

Citations

0
Hypoxia-induced PRMT1 methylates HIF2β to promote breast tumorigenesis via enhancing glycolytic gene transcription DOI Creative Commons
Wenjuan Li,

Yan-Chao Chen,

Yian Lin

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(4), P. 115487 - 115487

Published: April 1, 2025

Hypoxia-induced metabolic reprogramming is closely linked to breast cancer progression. Through transcriptomic analysis, we identified PRMT1 as a direct target of hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions in cells. In turn, enhances the expression HIF1α-driven glycolytic genes. Mechanistically, methylates HIF2β at arginine 42, facilitating formation, chromatin binding, and transcriptional activity HIF1α/HIF2β heterodimer. Genetic pharmacological inhibition suppresses methylation, heterodimer gene expression, lactate production, malignant behaviors Moreover, combination treatment with iPRMT1, inhibitor, menadione, an HIF1α/P300 interaction demonstrates synergistic effects suppressing tumor growth. Clinically, PRMT1-mediated methylation were significantly elevated tumors compared adjacent normal tissues. conclusion, our findings reveal critical role reprogramming,

Language: Английский

Citations

0
Overview of PRMT1 Modulators: Inhibitors and Degraders DOI
Jun Wu,

Deping Li,

Li‐Fang Wang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 279, P. 116887 - 116887

Published: Sept. 20, 2024

Language: Английский

Citations

3