Reticulocalbin 3 Is a Novel Mediator of Glioblastoma Progression DOI Open Access
Yi He, Salvador Alejo, Jessica D. Johnson

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(7), P. 2008 - 2008

Published: March 28, 2023

Glioblastoma is the most common malignant primary brain tumor. Molecular mechanisms underlying pathobiology of glioblastoma are incompletely understood, emphasizing an unmet need for identification new therapeutic candidates. Reticulocalbin 3 (RCN3), ER lumen-residing Ca2+ binding protein, plays essential role in protein biosynthesis processes via secretory pathway. Emerging studies demonstrated that RCN3 a target intervention various diseases. However, knowledge gap exists about whether glioblastoma. Publicly available datasets suggest overexpressed and portends poor survival rates. The knockdown or knockout using shRNA CRISPR/Cas9 gRNA, respectively, significantly reduced proliferation, neurosphere formation, self-renewal GSCs. RNA-seq showed downregulation genes related to translation, ribosome, cytokine signaling upregulation immune response, stem cell differentiation, extracellular matrix (ECM) cells. Mechanistic qRT-PCR decreased expression ribosomal increased stress genes. Further, silico analysis patient correlated with ECM, response pathway Importantly, enhanced tumor-bearing mice orthotopic models. Our study suggests could be potential development

Language: Английский

Epigenetic regulation in cancer therapy: From mechanisms to clinical advances DOI Creative Commons
Lei Tao, Yue Zhou, Yuan Luo

et al.

MedComm – Oncology, Journal Year: 2024, Volume and Issue: 3(1)

Published: Jan. 4, 2024

Abstract Epigenetic regulation refers to the alteration of gene expression independent changes in DNA sequence. It involves chemical modifications such as methylation, histone and acetylation, which are regulated by a coordinated interplay various regulators ensure precise spatial temporal expression. aberrations commonly observed cancer considered hallmarks cancer. In recent years, small molecules targeting specific epigenetic have been developed demonstrating promising therapeutic potential preclinical clinical trials for treatment. this review, we summarize essential regulatory mechanisms dysfunctions involved acetylation during tumor development progression. Moreover, discuss current advances challenges therapy that target these both hematologic malignancies solid tumors. Finally, combining drugs with other therapies, including chemotherapy, radiotherapy, targeted therapy, immunotherapy, approach Overall, aim enhance understanding explore strategies based on mechanisms, ultimately advance improve patient prognosis.

Language: Английский

Citations

19
Current and future therapeutic strategies for high-grade gliomas leveraging the interplay between epigenetic regulators and kinase signaling networks DOI Creative Commons
Lea Stitzlein,

Jack T. Adams,

Erin N. Stitzlein

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: Jan. 5, 2024

Targeted therapies, including small molecule inhibitors directed against aberrant kinase signaling and chromatin regulators, are emerging treatment options for high-grade gliomas (HGG). However, when translating these into the clinic, their efficacy is generally limited to partial transient responses. Recent studies in models of reveal a convergence epigenetic regulators networks that often cooperate promote malignant properties drug resistance. This review examines interplay between five well-characterized groups histone deacetylase (HDAC) family, bromodomain extraterminal (BET)-containing proteins, protein arginine methyltransferase (PRMT) Enhancer zeste homolog 2 (EZH2), lysine-specific demethylase 1 (LSD1), various pathways essential cancer cell growth progression. These specific were chosen due targetability via pharmacological intervention clinical relevance. Several have demonstrated improved from dual inhibition kinases. Overall, interactions likely influenced by several factors, individual glioma subtypes, preexisting mutations, overlapping/interdependent functions regulators. The insights gained understanding how genome epigenome will guide design future therapeutic strategies utilize with overall survival.

Language: Английский

Citations

8
Pharmacological inhibition of KDM1A/LSD1 enhances estrogen receptor beta-mediated tumor suppression in ovarian cancer DOI Creative Commons

Prabhakar Pitta Venkata,

Sridharan Jayamohan, Yi He

et al.

Cancer Letters, Journal Year: 2023, Volume and Issue: 575, P. 216383 - 216383

Published: Sept. 13, 2023

Language: Английский

Citations

13
Epigenetic reprogramming in pediatric gliomas: from molecular mechanisms to therapeutic implications DOI
Santiago Haase, Stephen V. Carney, María L. Varela

et al.

Trends in cancer, Journal Year: 2024, Volume and Issue: 10(12), P. 1147 - 1160

Published: Oct. 10, 2024

Language: Английский

Citations

5
PRMT5 inhibition sensitizes glioblastoma tumor models to temozolomide DOI Creative Commons
Shumpei Onishi, Sridharan Jayamohan,

Ashis Chowdhury

et al.

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

Published: Feb. 10, 2025

Background: Despite multi-model therapy of maximal surgical resection, radiation, chemotherapy, and tumor-treating fields, glioblastoma patients show dismal prognosis. Protein Arginine Methyltransferase 5 (PRMT5) is overexpressed in its inhibition imparts an anti-tumor effect. Even though Temozolomide (TMZ) the standard chemotherapeutic agent treatment glioblastoma, tumor cells invariably develop resistance to TMZ. However, mechanistic role PRMT5 unknown. Methods: Patient-derived primary neurospheres (GBMNS), treated with inhibitor (LLY-283) or transfected target-specific siRNA were TMZ subjected vitro functional studies. The intracranial mouse xenograft model was used test vivo antitumor efficacy combination treatment. Results: We found that increased cytotoxic effect caspase 3/7 activity GBMNS suggesting apoptosis potential mode cell death abrogated TMZ-induced G2/M cycle arrest. Unbiased transcriptomic studies indicate negatively enriches DNA damage repair genes. Importantly, double-strand breaks (ɣH2AX foci) enhanced (comet assay), increases damage. Specifically, LLY-283 blocked homologous recombination GBMNS. In , significantly curbed growth prolonged survival tumor-bearing mice. Conclusion: Concomitant has greater efficacy, could be a new therapeutic strategy for glioblastoma.

Language: Английский

Citations

0
The epigenetic mechanisms involved in the treatment resistance of glioblastoma DOI Open Access

Aanya Shahani,

Hasan Slika, Ahmed Elbeltagy

et al.

Cancer Drug Resistance, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

Glioblastoma (GBM) is an aggressive malignant brain tumor with almost inevitable recurrence despite multimodal management surgical resection and radio-chemotherapy. While several genetic, proteomic, cellular, anatomic factors interplay to drive promote treatment resistance, the epigenetic component remains among most versatile heterogeneous of these factors. Herein, landscape GBM refers a myriad modifications processes that can alter gene expression without altering genetic code cancer cells. These encompass DNA methylation, histone modification, chromatin remodeling, non-coding RNA molecules, all which have been found be implicated in augmenting tumor’s behavior driving its resistance therapeutics. This review aims delve into underlying interactions mediate this role for each components. Further, it discusses two-way relationship between heterogeneity plasticity, are crucial effectively treat GBM. Finally, we build on previous characterization explore specific targets investigated development promising therapeutic agents.

Language: Английский

Citations

0
Clusterin-mediated polarization of M2 macrophages: a mechanism of temozolomide resistance in glioblastoma stem cells DOI Creative Commons

Jianping Wen,

Xia Wu,

Zhicheng Shu

et al.

Stem Cell Research & Therapy, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 24, 2025

Glioblastoma remains one of the most lethal malignancies, largely due to its resistance standard chemotherapy such as temozolomide. This study investigates a novel mechanism involving glioblastoma stem cells (GSCs) and polarization M2-type macrophages, mediated by extracellular vesicle (EV)-based transfer Clusterin. Using 6-week-old male CD34+ humanized huHSC-(M-NSG) mice (NM-NSG-017) cell lines (T98G U251), we demonstrated that GSC-derived EVs enriched with Clusterin induce M2 macrophage polarization, thereby enhancing temozolomide in cells. Single-cell transcriptome sequencing revealed close interactions between GSCs highlighting key mediator. Our findings indicate Clusterin-rich from drive proliferation modulating phenotypes. Targeting this pathway could potentially reverse mechanisms, offering promising therapeutic approach for glioblastoma. not only sheds light on critical underpinning but also lays groundwork developing therapies targeting tumor microenvironment. results suggest paradigm shift understanding resistance, emphasizing potential disrupting EV-mediated communication

Language: Английский

Citations

0
Lysine-specific demethylase 1 as a therapeutic cancer target: observations from preclinical study DOI
Jessica D. Johnson, Salvador Alejo, Sridharan Jayamohan

et al.

Expert Opinion on Therapeutic Targets, Journal Year: 2023, Volume and Issue: 27(12), P. 1177 - 1188

Published: Nov. 24, 2023

Lysine-specific histone demethylase 1A (KDM1A/LSD1) has emerged as an important therapeutic target in various cancer types. LSD1 regulates a wide range of biological processes that influence development, progression, metastasis, and therapy resistance. However, recent studies have revealed novel aspects biology, shedding light on its involvement immunogenicity, antitumor immunity, DNA damage response. These emerging findings the potential to be leveraged design effective LSD1-targeted therapies.

Language: Английский

Citations

4
Epigenetic Inhibitors as Alzheimer’s Disease Therapeutic Agents DOI Open Access
Yasunobu Yamashita, Yukihiro Itoh, Yuri Takada

et al.

Chemical and Pharmaceutical Bulletin, Journal Year: 2024, Volume and Issue: 72(7), P. 630 - 637

Published: June 30, 2024

Alzheimer's disease (AD) is the leading cause of senile dementia, and rapid increase in frequency AD cases has been attributed to population aging. However, current drugs have difficulty adequately suppressing symptoms there still a medical need for symptomatic agents. On other hand, it recently become clear that epigenetic dysfunctions are deeply involved development cognitive impairments. Therefore, epigenetics-related proteins attracted much attention as drug targets AD. Early-developed inhibitors were inappropriate treatment because their limited potential oral administration, blood-brain barrier penetration, high target selectivity, sufficient dose-limiting toxicity which essential properties small molecule targeting chronic neurodegenerative diseases such In recent years, discovery studies actively performed overcome problems several novel interest promising therapeutic Here, we review histone deacetylase (HDAC), lysine-specific demethylase 1 (LSD1) or bromodomains extra-terminal domain (BET) protein, enable memory function improvement model mice.

Language: Английский

Citations

1
Multiple Comprehensive Analyses Identify Lysine Demethylase KDM as a Potential Therapeutic Target for Pancreatic Cancer DOI Creative Commons

Wan‐Jou Shen,

Hsuan-Min Kao,

Chih‐Yang Wang

et al.

International Journal of Medical Sciences, Journal Year: 2024, Volume and Issue: 21(11), P. 2158 - 2169

Published: Jan. 1, 2024

Pancreatic cancer (PC) is a challenging and heterogeneous disease with high mortality rate. Despite advancements in treatment, the prognosis for PC patients remains poor, chance of recurrence. Biomarkers are crucial diagnosing cancer, predicting patient selecting treatments. However, current lack effective biomarkers could contribute to insufficiency existing These findings underscore urgent need develop novel strategies fight this disease. This study utilized multiple comprehensive bioinformatic analyses identify potential therapeutic target genes PC, focusing on histone lysine demethylases (KDMs). We found that expression levels KDM family genes, particularly KDM1A, KDM5A KDM5B, were associated improved overall survival cohort. Furthermore, infiltration various immune cells, including B neutrophils, CD8

Language: Английский

Citations

1