Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma DOI Creative Commons
Lucas D. Caeiro,

Yuichiro Nakata,

Rodrigo L. Borges

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 6, 2023

Abstract Approximately 20% of head and neck squamous cell carcinomas (HNSCC) exhibit reduced methylation on lysine 36 histone H3 (H3K36me) due to mutations in methylase NSD1 or a lysine-to-methionine mutation (H3K36M). Whether such alterations H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M divided into two groups: those display aberrant accumulation H3K27me3 maintain steady levels H3K27me3. The first group shows decreased proliferation, genome instability, increased sensitivity genotoxic agents, as PARP1/2 inhibitors. In contrast, the with do not these characteristics unless are elevated, either by DNA hypomethylating agents inhibiting demethylases KDM6A/B. Mechanistically, found reduces directly impeding activities methyltransferase NSD3 demethylase LSD2. Notably, induced expression bona fide epigenetic mark since it requires continuous inherited. Moreover, inhibitors solely depends levels. Indeed, aberrantly high decrease BRCA1 FANCD2-dependent repair, resulting higher breaks replication stress. Finally, support our vitro findings, inhibitor alone reduce tumor burden xenograft model elevated H3K27me3, whereas consistent levels, combination upregulate proves successful. conclusion, findings underscore delicate balance between H3K36 H3K27 methylation, essential maintaining stability. This equilibrium presents promising opportunities patients H3K36me-deficient tumors.

Language: Английский

MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis DOI Creative Commons
Alicia Llorente Lope, Maria Blasco, Irene Espuny

et al.

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(12), P. 1833 - 1847

Published: Nov. 9, 2023

Abstract MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER + ) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility functional assays from human syngeneic mouse models to show directly interacts with receptor alpha (ERα), thereby promoting a unique landscape favours metastatic spread. We identify metastasis-promoting genes de novo licensed following exposure in MAF-dependent manner. The histone demethylase KDM1A is key epigenomic remodelling facilitates expression pro-metastatic MAF/oestrogen-driven gene program, loss activity prevents this metastasis. thus determined molecular basis underlying MAF/oestrogen-mediated genetic, epigenetic hormone signals systemic environment, which influence ability cells metastasize.

Language: Английский

Citations

3
Advancing breast cancer diagnosis with a near-infrared fluorescence imaging smart sensor for estrogen/progesterone receptor detection DOI Creative Commons

Gong Zhang,

Min Dong,

Xiulei Yao

et al.

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Nov. 30, 2023

Abstract Molecular-genetic imaging has greatly advanced clinical diagnosis and prognosis monitoring. However, the specific visualization of intracellular proteins such as estrogen receptor (ER) progesterone (PR) remains an elusive goal. Here, we highlight a novel method for selectively detecting ER/PR positive tumors using genetically engineered responsive elements. Our study demonstrates that double elements exhibit most sensitivity to steroid receptors in breast cancers. By utilizing cationic polymer vector, constructed element-fluorescence protein system can image cancers murine models under near-infrared laser. This non-invasive achieved high-resolution detection without death or serious anaphylactic activity animals. findings suggest reporter consisting response provides practical identifying biomarkers advancing cancer therapy.

Language: Английский

Citations

3
Comprehensive analysis of REST corepressors (RCORs) in pan-cancer DOI Creative Commons
Rong Zheng,

Yingying Pan,

Xinhui Liu

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: June 5, 2023

REST corepressors (RCORs) are the core component of LSD1/CoREST/HDACs transcriptional repressor complex, which have been revealed differently expressed in various cancers, but therapeutic and prognostic mechanisms cancer still poorly understood. In this study, we analyzed expression, value, molecular subtypes, genetic alteration, immunotherapy response drug sensitivity RCORs pan-cancer. Clinical correlation, stemness index, immune infiltration regulatory networks hepatocellular carcinoma (HCC) were detected through TCGA GSCA database. In-vitro experiments conducted to explore role RCOR1 HCC cells. The expression varied among different values several cancers. Cancer subtypes categorized according with clinical information. significantly correlated response, MSI, alteration HCC, considered as potential predictor also had association infiltration. ceRNA-TF-kinase constructed. Besides, acts an oncogene promotes proliferation cells by inhibiting cell cycle arrest apoptosis. Taken together, our study pan-cancer, offering a benchmark for disease-related research.

Language: Английский

Citations

1
The catalytic-independent function of LSD1 modulates the epigenetic landscape of mouse embryonic stem cells DOI Open Access
Sandhya Malla, Kanchan Kumari, Carlos Martinez‐Gamero

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 29, 2023

Abstract Lysine-specific histone demethylase 1 (LSD1), which demethylates mono- or di-methylated H3 on lysine 4 (H3K4me1/2), is essential for early embryogenesis and development. Here we show that LSD1 dispensable embryonic stem cell (ESC) self-renewal but required ESC growth differentiation. Reexpression of a catalytically-dead (LSD1 MUT ) recovers the proliferation capability ESCs, yet enzymatic activity to ensure proper Indeed, gain H3K4me1 in Lsd1 knockout (KO) ESCs does not lead major changes global gene expression programs related stemness. However, ablation results decreased DNMT1 UHRF1 proteins coupled hypomethylation. We both control protein stability through interaction with ubiquitin-specific peptidase 7 (USP7) and, consequently, inhibiting ubiquitylation. Our studies elucidate first time novel mechanism by scaffolding function controls DNA methylation ESCs.

Language: Английский

Citations

1
CoREST Complex Inhibition Alters RNA Splicing to Promote Neoantigen Expression and Enhance Tumor Immunity DOI Open Access
Robert Fisher, Kihyun Park, Kwangwoon Lee

et al.

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

Published: Dec. 12, 2024

ABSTRACT Epigenetic complexes tightly regulate gene expression and colocalize with RNA splicing machinery; however, the consequences of these interactions are uncertain. Here, we identify unique CoREST repressor complex factors their functional in tumorigenesis. Using mass spectrometry, vivo binding assays, cryo-EM find that complex-splicing factor direct perturbed by inhibitor, corin, leading to extensive changes melanoma other malignancies. predictive machine learning models MHC IP-MS, thousands corin-induced neopeptides derived from unannotated splice sites which generate immunogenic splice-neoantigens. Furthermore, corin reactivates response immune checkpoint blockade promotes dramatic expansion cytotoxic T cells an cold model. inhibition thus represents a therapeutic opportunity cancer creates tumor-associated neoantigens enhance immunogenicity current therapeutics. Statement Significance We novel role transcriptional regulating pre-mRNA small molecule alternative events neoantigen cell-mediated immunity. This potential approach promote immunoreactive immune-cold tumors.

Language: Английский

Citations

0
The CoREST complex inhibitor, corin, leads to decreased tumor growth, increased cellular differentiation and extended lifespan in atypical teratoid rhabdoid tumor xenograft models DOI Open Access
Anupa Geethadevi,

Nikhil Vaidya,

Robert Fisher

et al.

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

Published: Dec. 17, 2024

Abstract Background Atypical teratoid rhabdoid tumor (ATRT) is the most common malignant brain in infants, and more than 60% of children with ATRT die from their tumor. associated mutational inactivation/deletion SMARCB1 , a member SWI/SNF chromatin remodeling complex, suggesting that epigenetic events play critical role development progression. Moreover, disruption allows unopposed activity repressors, which contribute to tumorigenicity. We therefore explored CoREST repressor complex ATRT. Methods evaluated effects bifunctional LSD1/HDAC1/2 small molecule inhibitor, corin, on cell growth, apoptosis, differentiation, gene expression accessibility. Results found corin inhibited growth cells regardless subgroup, was increased apoptosis differentiation. ATAC-seq showed increases accessibility corin-treated cells, changes seen at genes neuronal differentiation synaptic function. RNA-seq confirmed decreased DNA replication/cell cycle-associated treated corin. Corin suppressed orthotopic leading significant extension lifespan. In addition, histone acetylation (H3K9ac, H3K27ac) methylation (H3K4Me1) xenografts, consistent on-target pharmacodynamics. Conclusion The suppresses induces promotes ATRT, significantly survival mice bearing xenografts. Our results suggest potential application inhibitors patients Key Points inhibition by leads inhibits extends lifespan animal models Importance Study Loss function hallmark dysfunction mammalian an inability counteract complexes. functions as represses during development. Inhibition induction These are reverses primary block maintains stem state contributes tumorigenesis. studies improve our understanding how therapeutically address underlying drivers support further for

Language: Английский

Citations

0
The molecular determinants of phenotypic plasticity in homeostasis and neoplasia DOI Creative Commons

Bradley Balk,

David W. Goodrich

Published: Dec. 13, 2024

Phenotypic plasticity, the capacity of cells to transition between distinct phenotypic and lineage states over time, is a genetically epigenetically encoded trait essential for normal development adult tissue homeostasis. In cancer, plasticity programs can be deployed aberrantly enable disease progression acquired therapeutic resistance. Cancer current barrier achieving cures advanced cancers using available molecularly targeted therapies. This review summarizes complex interconnected molecular pathways implicated in both context homeostasis cancer. Molecular convergent these contexts are highlighted while enabling distinguished from those that specify phenotype already plastic cells. Key unresolved questions field discussed along with emerging technologies may used help answer them.

Language: Английский

Citations

0
Switching under selection: how CoREST controls endocrine therapy resistance in ER+ breast cancer DOI
Brent Chick, Diana C. Hargreaves

Nature Structural & Molecular Biology, Journal Year: 2022, Volume and Issue: 29(11), P. 1040 - 1042

Published: Nov. 1, 2022

Language: Английский

Citations

1
Histone deacetylases and other epigenetic targets DOI

Fabrizio Carta

Elsevier eBooks, Journal Year: 2023, Volume and Issue: unknown, P. 265 - 281

Published: Sept. 8, 2023

Language: Английский

Citations

0
Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma DOI Creative Commons
Lucas D. Caeiro,

Yuichiro Nakata,

Rodrigo L. Borges

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 6, 2023

Abstract Approximately 20% of head and neck squamous cell carcinomas (HNSCC) exhibit reduced methylation on lysine 36 histone H3 (H3K36me) due to mutations in methylase NSD1 or a lysine-to-methionine mutation (H3K36M). Whether such alterations H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M divided into two groups: those display aberrant accumulation H3K27me3 maintain steady levels H3K27me3. The first group shows decreased proliferation, genome instability, increased sensitivity genotoxic agents, as PARP1/2 inhibitors. In contrast, the with do not these characteristics unless are elevated, either by DNA hypomethylating agents inhibiting demethylases KDM6A/B. Mechanistically, found reduces directly impeding activities methyltransferase NSD3 demethylase LSD2. Notably, induced expression bona fide epigenetic mark since it requires continuous inherited. Moreover, inhibitors solely depends levels. Indeed, aberrantly high decrease BRCA1 FANCD2-dependent repair, resulting higher breaks replication stress. Finally, support our vitro findings, inhibitor alone reduce tumor burden xenograft model elevated H3K27me3, whereas consistent levels, combination upregulate proves successful. conclusion, findings underscore delicate balance between H3K36 H3K27 methylation, essential maintaining stability. This equilibrium presents promising opportunities patients H3K36me-deficient tumors.

Language: Английский

Citations

0