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

The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma DOI Creative Commons

Muzhou Wu,

Ailish Hanly,

Frederick Gibson

et al.

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(6)

Published: Feb. 1, 2024

Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown be altered in therapy-resistant melanomas and other cancers, a specific targetable mechanism has not been validated. Here, we evaluated corepressor for element 1-silencing transcription factor (CoREST) repressor complex recently developed bivalent inhibitor corin within context of phenotype plasticity therapeutic resistance. We found that CoREST was critical mediator major distinct phenotypes treatment cells led reprogramming. Global assessment transcript chromatin changes conferred by revealed effects on histone marks connected epithelial-mesenchymal transition-associated (EMT-associated) factors dual-specificity phosphatases (DUSPs). Remarkably, BRAF inhibitor-resistant (BRAFi-R) promoted resensitization BRAFi therapy. DUSP1 consistently downregulated BRAFi-R melanomas, which reversed associated inhibition p38 activity therapies. Moreover, this recapitulated BIRB 796. These findings identify as central targeted therapy suggest may prove beneficial BRAFi-resistant melanoma.

Language: Английский

Citations

10
The scaffolding function of LSD1 controls DNA methylation in mouse ESCs DOI Creative Commons
Sandhya Malla, Kanchan Kumari, Carlos A. García‐Prieto

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 5, 2024

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 mouse embryonic stem cell (ESC) self-renewal but required ESC growth differentiation. Reintroduction of a catalytically-impaired (LSD1

Language: Английский

Citations

6
Epigenetic mechanisms of cancer progression and therapy resistance in estrogen-receptor (ER+) breast cancer DOI Creative Commons
Eneda Toska

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: 1879(3), P. 189097 - 189097

Published: March 20, 2024

Estrogen receptor-positive (ER+) breast cancer is the most frequent subtype. Agents targeting ER signaling pathway have been successful in reducing mortality from for decades. However, mechanisms of resistance to these treatments arise, especially metastatic setting. Recently, it has recognized that epigenetic dysregulation a common feature facilitates acquisition hallmarks across types, including ER+ cancer. Alterations regulators and transcription factors (TF) coupled with changes chromatin landscape found orchestrate oncogenesis, metastasis, development resistant phenotype. Here, we review recent advances our understanding how epigenome dictates tumorigenesis targeted therapies discuss novel therapeutic interventions overcoming resistance.

Language: Английский

Citations

5
Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma DOI Open Access
Lucas D. Caeiro,

Yuichiro Nakata,

Rodrigo L. Borges

et al.

Genes & Development, Journal Year: 2024, Volume and Issue: 38(1-2), P. 46 - 69

Published: Jan. 1, 2024

Approximately 20% of head and neck squamous cell carcinomas (HNSCCs) 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 former group exhibits proliferation, genome instability, heightened sensitivity genotoxic agents like PARP1/2 inhibitors. Conversely, with constant lack these characteristics unless elevated by DNA hypomethylating inhibiting demethylases KDM6A/B. Mechanistically, reduces directly impeding the activities methyltransferase NSD3 demethylase LSD2. Notably, induced expression are not bona fide epigenetic mark because they require continuous inherited. Moreover, increased inhibitors depends solely diminishing BRCA1- FANCD2-dependent repair. Finally, inhibitor alone tumor burden xenograft model H3K27me3, whereas consistent combination up-regulate proves successful. These findings underscore crucial balance between H3K36 H3K27 maintaining offering new options patients H3K36me-deficient tumors.

Language: Английский

Citations

4
Epigenetic Landscapes of Aging in Breast Cancer Survivors: Unraveling the Impact of Therapeutic Interventions—A Scoping Review DOI Open Access
Nikita Nikita, Zhengyang Sun, Swapnil Sharma

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(5), P. 866 - 866

Published: March 3, 2025

Breast cancer therapies have dramatically improved survival rates, but their long-term effects, especially on aging survivors, need careful consideration. This review delves into how breast treatments and intersect, focusing the epigenetic changes triggered by chemotherapy, radiation, hormonal treatments, targeted therapies. Treatments can speed up biological altering DNA methylation, histone modifications, chromatin remodeling, affecting gene expression without changing sequence itself. The explains double-edged sword effect of therapy-induced which help fight also accelerate aging. Chemotherapy therapies, in particular, impact methylation promoting chronic inflammation shortening telomeres. These increase age, as seen clocks biomarkers like p21, play roles drug resistance therapeutic decisions. Chronic inflammation, driven higher levels inflammatory cytokines such TNF-α IL-6 well telomere shortening, significantly contributes to characteristics survivors. Non-coding RNAs, including microRNAs long non-coding are crucial regulating pathways altered these treatments. explores new targeting changes, inhibitors, deacetylase microRNA-based reduce effects therapy. Non-drug approaches, dietary lifestyle show promise combating It highlights clinical signs aging-related side heart lung problems, endocrine reproductive issues, reduced quality life. development comprehensive methods CHEMO-RADIAT score predict major cardiovascular events after therapy is discussed. Understanding caused offers valuable insights for creating interventions enhance health span life Continued research fully understand alterations impacts.

Language: Английский

Citations

0
The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors DOI Creative Commons
Imad Soukar, Robert Fisher, Sanjana Bhagavatula

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 24, 2025

Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma that may be seen in patients with neurofibromatosis type 1 (NF1) or occur sporadically. While surgery the primary treatment for localized MPNST 61.9% overall survival rate, metastatic disease often fatal due to resistance systemic therapies which underscores urgent need effective treatments. MPNSTs frequently harbor inactivating driver mutations PRC2 epigenetic repressor complex suggesting represent specific vulnerability these tumors. Here, we investigate role of LSD1-HDAC1-CoREST (LHC) mediating growth and progression. Our findings demonstrate LHC small molecule inhibitor, corin, induces apoptosis significantly inhibits proliferation cells. Transcriptomic analysis corin-treated cells demonstrates increases genes associated axonogenesis neuronal differentiation as well altered extracellular matrix; additionally, corin shown inhibit invasion vitro. These results underscore critical facilitating progression suggest targeting represents promising therapeutic approach this malignancy.

Language: Английский

Citations

0
Enhanced desmosome assembly driven by acquired high-level desmoglein-2 promotes phenotypic plasticity and endocrine resistance in ER+ breast cancer DOI

Bohan Liu,

Yuting Liu, Shuang Yang

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 600, P. 217179 - 217179

Published: Aug. 22, 2024

Language: Английский

Citations

3
Relationship between histone demethylase LSD family and development and prognosis of gastric cancer DOI Creative Commons
Liyan Dong, Jiaxing Zhu,

Anyi Deng

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 3, 2023

Objective to elucidate the correlation between histone demethylase and gastric cancer Research object Results As one of important regulatory mechanisms in molecular biology epigenetics, modification plays an role including downstream gene expression regulation epigenetics effect. Both methyltransferase demethylases are involved formation maintaining different methylation status, which turn through a variety vital molecules signaling pathways recognition caused by biological process, eventually participate chromatin function, with physiological activities, especially closely related occurrence embryonic development. Conclusion This paper intends review research progress this field from aspects protein structure, catalytic mechanism function LSD1 LSD2, order provide theoretical reference for further understanding exploration development prognosis cancer.

Language: Английский

Citations

7
The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors DOI Open Access
Imad Soukar, Robert Fisher, Sanjana Bhagavatula

et al.

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

Published: Aug. 19, 2024

Abstract Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma that may be seen in patients with neurofibromatosis type 1 (NF1) or occur sporadically. While surgery the primary treatment for localized MPNST 61.9% overall survival rate, metastatic disease often fatal due to resistance systemic therapies which underscores urgent need effective treatments. MPNSTs frequently harbor inactivating driver mutations PRC2 epigenetic repressor complex suggesting represent specific vulnerability these tumors. Here, we investigate role of LSD1-HDAC1-CoREST (LHC) mediating growth and progression. Our findings demonstrate LHC small molecule inhibitor, corin, induces apoptosis significantly inhibits proliferation cells. Transcriptomic analysis corin-treated cells demonstrates increases genes associated axonogenesis neuronal differentiation as well altered extracellular matrix; additionally, corin shown inhibit invasion vitro. These results underscore critical facilitating progression suggest targeting represents promising therapeutic approach this malignancy.

Language: Английский

Citations

2
RCOR1 is targeted by miR-23b-3p to modulate growth, colony formation, migration, and invasion of prostate cancer cells DOI Open Access
Chenli Liu

International Journal of Clinical and Experimental Pathology, Journal Year: 2024, Volume and Issue: 17(2), P. 29 - 38

Published: Jan. 1, 2024

Prostate cancer holds the second-highest incidence rate among all male malignancies, with a noticeable scarcity of effective treatment approaches. The REST Corepressor 1 (RCOR1) protein exhibits elevated expression across various tumors, acting as an oncogene. Nevertheless, its functions and mechanisms in prostate have yet to be documented. While miR-23 demonstrates reduced cancer, downstream genes it regulates remain unclear.

Language: Английский

Citations

1