Interplay Between the Histone Variant H2A.Z and the Epigenome in Pancreatic Cancer

Ávila-López, Pedro A; Nuñez-Martínez, Hober N.; Peralta‐Álvarez, Carlos Alberto; Martínez‐Calvillo, Santiago; Recillas‐Targa, Félix; Hernández‐Rivas, Rosaura

doi:10.1016/j.arcmed.2022.11.010

Cited by 5 publications

(4 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SEs play a crucial role in sustaining robust transcriptional activation of key oncogenes vital to PDAC development and progression. 66 RNAPOLII expression is intrinsically linked to SEs in PDAC. 67 Oncogenes associated with or driven by SEs were highly susceptible to CDK7 inhibition in PDAC, underscoring the potential of transcription-disrupting strategies by targeting SEs to suppress PDAC.…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super‐enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis‐generating study

Huang,

Yang,

Chen

et al. 2023

Clinical & Translational Med

View full text Add to dashboard Cite

BackgroundInhibition of CDK7, a potent transcription regulator, may bring new hope for treating pancreatic ductal adenocarcinoma (PDAC), which is featured by large genetic heterogeneity and abundant KRAS mutations. This investigation aimed at exploring the discrepant efficacies of THZ1, a small‐molecule covalent CDK7 inhibitor, on PDACs with different KRAS mutations and the underlying mechanisms.MethodsAssociations of CDK7 expression with survival by KRAS mutations were first assessed. Effects of THZ1 on PDAC by different KRAS mutations were then investigated in vitro and in vivo. Moreover, the effects of THZ1 on gene transcription and phosphorylation of RNA polymerase II (RNAPOLII) in different KRAS mutant PDACs were assessed, and the effect of THZ1 on super‐enhancer activity was evaluated using chromatin immunoprecipitation sequencing. Lastly, the effects of THZ1 on the binding of H3K27ac to PIK3CA and on the PI3K/AKT/mTOR signalling were analysed.ResultsHigh CDK7 expression was significantly linked to worse survival within PDAC patients carrying KRAS‐G12V mutation but not in those with KRAS‐G12D mutation. The apoptosis‐inducing effect of THZ1 was markedly stronger in KRAS‐G12V PDAC than KRAS‐G12D cancer. THZ1 significantly inhibited the growth of xenograft tumour with KRAS‐G12V mutation, and the inhibition was markedly stronger than for KRAS‐G12D tumour. In mini‐cell‐derived xenograft (CDX) models, THZ1 significantly suppressed KRAS‐G12V PDAC but not KRAS‐G12D cancer. THZ1 significantly suppressed the phosphorylation of RNAPOLII, and this effect was stronger in KRAS‐G12V PDAC (especially at ser5). KRAS‐G12V PDAC had more H3K27ac‐binding super‐enhancers, and the inhibition of THZ1 on super‐enhancer activity was also stronger in KRAS‐G12V PDAC. Furthermore, THZ1 significantly weakened the binding of H3K27ac to PIK3CA in KRAS‐G12V PDAC. THZ1 significantly suppressed the PI3K/AKT/mTOR pathway and its downstream markers, and this effect was stronger in KRAS‐G12V cells.ConclusionsIn this hypothesis‐generating study, THZ1 might selectively inhibit certain PDACs with KRAS‐G12V mutation more potently compared with some other PDACs with KRAS‐G12D mutation, which might be associated with its effect on super‐enhancer activity and the PI3K/AKT/mTOR signalling. Our findings might offer novel key clues for the precise management of PDAC and important evidence for future targeted trial design.Highlights THZ1 had a stronger effect on PDAC‐bearing KRAS‐G12V mutation than G12D mutation. Suppressive effect of THZ1 on phosphorylation of RNAPOLII was stronger in KRAS‐G12V than KRAS‐G12D PDAC. Inhibition of THZ1 on super‐enhancer activity and H3K27ac binding to PIK3CA was stronger in KRAS‐G12V PDAC. Suppressive effect of THZ1 on PI3K/AKT/mTOR pathway was stronger in KRAS‐G12V PDAC.

show abstract

Section: Discussionmentioning

confidence: 98%

“…The complexes can then bind with promoter and enhancer regions on DNA, resulting in the abnormal transcription activation of oncogenes. SEs play a crucial role in sustaining robust transcriptional activation of key oncogenes vital to PDAC development and progression 66 . RNAPOLII expression is intrinsically linked to SEs in PDAC 67 .…”

Section: Discussionmentioning

confidence: 99%

The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super‐enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis‐generating study

Huang,

Yang,

Chen

et al. 2023

Clinical & Translational Med

View full text Add to dashboard Cite

show abstract

“…Histone variants H2A.Z and H3.3, are frequently placed in the same nucleosomes and cooperate to regulate transcription 39 . As H2A.Z can be an oncogenic driver, we explored the role of H2A.Z in DIPG cells after HDAC inhibition 40,41 . We show that many of H2A.Z and H3.3K27M ChIP-seq peaks overlap with each other in DIPG cells at genes with a low constitutive expression.…”

Section: Discussionmentioning

confidence: 99%

“…The unstable H3.3-H2A.Z nucleosomes might be even more affected when H3.3 is substituted with the H3.3K27M oncohistone. However, it is equally possible that the presence of H2A.Z, and particularly its hyperacetylated form, might recruit some additional proteins, like RNA polymerase II and other partners that will additionally alter gene expression or induce turnover of H3.3K27M containing nucleosomes 40 . Future studies will focus on precise dissecting of the H2A.Z role in the H3.3K27M stability and turnover.…”

Section: Discussionmentioning

confidence: 99%

H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in paediatric high-grade glioma cells

Leszczynska

Freitas

Jayaprakash

et al. 2023

Preprint

View full text Add to dashboard Cite

Diffuse intrinsic pontine gliomas (DIPG) are deadly paediatric brain tumours, non-resectable due to brainstem localisation and diffusive growth. Patients with DIPG have a dismal prognosis of 9-12 months of survival with no effective therapy. Over 80% of DIPGs harbour a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine to methionine substitution (H3K27M). H3K27M causes global epigenetic alterations (a loss of H3K27 trimethylation and an increase in H3K27 acetylation) resulting in aberrant gene expression. To date, no therapeutic strategy exists to suppress the levels of oncogenic H3K27M. We show that pan-HDAC inhibitors (HDACi) lead to the temporary but significant reduction in the H3.3K27M protein (up to 80%) in multiple glioma cell lines expressing the H3.3K27M histone variant, without changes in the H3F3A mRNA expression. The H3.3K27M occupancy at the chromatin is greatly reduced upon HDACi (SB939) treatment, as shown by ChIPseq analysis. H3.3K27M loss is most striking at SB939-upregulated genes suggesting the role in repression of these genes. In addition, genes previously reported as H3K27M-dependent become downregulated in response to SB939 treatment. We discover that the SB939-mediated loss of H3.3K27M is partially blocked by a lysosomal inhibitor, chloroquine. Moreover, the loss of H3.3K27M is facilitated by co-occurrence of H2A.Z, as evidenced by the knock-down of H2A.Z histone isoforms. ChIPseq analysis confirms the occupancy of H3.3K27M and H2A.Z at the same SB939-inducible genes. Altogether, we provide new insight into disease-specific mechanism of HDAC inhibition and demonstrate pharmacological modulation of the oncogenic H3.3K27M protein levels. These findings open a new possibility to directly target the H3.3K27M oncohistone, which may be exploited in future therapies.

show abstract

Navigating glioblastoma complexity: the interplay of neurotransmitters and chromatin

Romero-Reyes,

Vázquez-Martínez,

Silva

et al. 2024

Mol Biol Rep

View full text Add to dashboard Cite

Glioblastoma is the most aggressive brain cancer with an unfavorable prognosis for patient survival. Glioma stem cells, a subpopulation of cancer cells, drive tumor initiation, self-renewal, and resistance to therapy and, together with the microenvironment, play a crucial role in glioblastoma maintenance and progression. Neurotransmitters such as noradrenaline, dopamine, and serotonin have contrasting effects on glioblastoma development, stimulating or inhibiting its progression depending on the cellular context and through their action on glioma stem cells, perhaps changing the epigenetic landscape. Recent studies have revealed that serotonin and dopamine induce chromatin modifications related to transcriptional plasticity in the mammalian brain and possibly in glioblastoma; however, this topic still needs to be explored because of its potential implications for glioblastoma treatment. Also, it is essential to consider that neurotransmitters’ effects depend on the tumor’s microenvironment since it can significantly influence the response and behavior of cancer cells. This review examines the possible role of neurotransmitters as regulators of glioblastoma development, focusing on their impact on the chromatin of glioma stem cells.

show abstract

Interplay Between the Histone Variant H2A.Z and the Epigenome in Pancreatic Cancer

Cited by 5 publications

References 86 publications

The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super‐enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis‐generating study

The suppressive efficacy of THZ1 depends on KRAS mutation subtype and is associated with super‐enhancer activity and the PI3K/AKT/mTOR signalling in pancreatic ductal adenocarcinoma: A hypothesis‐generating study

H2A.Z histone variants facilitate HDACi-dependent removal of H3.3K27M mutant protein in paediatric high-grade glioma cells

Navigating glioblastoma complexity: the interplay of neurotransmitters and chromatin

Contact Info

Product

Resources

About