Interference with the bromodomain epigenome readers drives p21 expression and tumor senescence
Liana P Webber1, Veronica Q Yujra2, Pablo A Vargas3
1Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, Ann Arbor, MI, 48109, USA; Department of Oral Pathology, School of Dentistry, Federal University of the Rio Grande do Sul, Porto Alegre, RS, 90035-004, Brazil.
Abstract:
Head and neck cancer (HNSCC) are one of the most common solid malignancies of the world, being responsible for over 350,000 deaths every year. Much of the complications in managing and treating HNSCC advent from the complex genetic and epigenetic landscape of the disease. Emerging information has shown promising results in targeting BRD4, an epigenetic regulator bromodomain that functions as a scaffold for transcription factors at promoters and super-enhancers. Here we show that by disrupting the interaction between BRD4 and histones using the bromodomain inhibitor JQ1, HNSCC cells undergo cell growth arrest followed by cellular senescence. Mechanistically, JQ1 negatively impacted the phosphorylation levels of SIRT1 along with the acetylation levels of mutant p53 (active). In vivo administration of JQ1 resulted in disruption of HNSCC growth along with the activation of cellular senescence, observed by the accumulation of DNA double-strand breaks, p16ink4, accumulation of senescence-associated beta-galactosidase, and loss of phosphorylated Sirt1ser47. Furthermore, we also demonstrate that JQ1 was efficient in reducing the population of cancer stem cells from HNSCC xenografts.
Insights
Targeting BRD4 with JQ1 halts head and neck squamous cell carcinoma (HNSCC) growth by inducing cellular senescence. This epigenetic approach also reduces cancer stem cells, offering a novel therapeutic strategy for HNSCC.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Head and neck squamous cell carcinoma (HNSCC) presents a significant global health challenge with over 350,000 annual deaths.
- The complex genetic and epigenetic alterations in HNSCC complicate treatment strategies.
- BRD4, an epigenetic regulator, is a promising therapeutic target due to its role in transcription factor scaffolding.
Purpose of the Study:
- To investigate the therapeutic potential of targeting BRD4 in HNSCC.
- To elucidate the mechanisms by which BRD4 inhibition affects HNSCC progression.
- To evaluate the efficacy of the BRD4 inhibitor JQ1 in preclinical models of HNSCC.
Main Methods:
- Utilized the bromodomain inhibitor JQ1 to disrupt BRD4-histone interactions in HNSCC cells.
- Assessed cellular responses including growth arrest and senescence.
- Analyzed molecular markers such as SIRT1 phosphorylation, p53 acetylation, DNA damage, p16ink4, and senescence-associated beta-galactosidase.
- Evaluated JQ1's efficacy in vivo using HNSCC xenografts and assessed cancer stem cell populations.
Main Results:
- JQ1 treatment induced cell growth arrest and cellular senescence in HNSCC cells.
- Mechanistically, JQ1 reduced SIRT1 phosphorylation and increased active mutant p53 acetylation.
- In vivo, JQ1 inhibited HNSCC tumor growth and promoted senescence.
- JQ1 treatment led to reduced cancer stem cell populations in HNSCC xenografts.
Conclusions:
- Disrupting BRD4-histone interactions with JQ1 is a viable strategy for HNSCC treatment.
- JQ1 induces HNSCC cell senescence and growth inhibition through specific molecular pathways.
- JQ1 demonstrates potential in reducing cancer stem cells, suggesting a role in preventing HNSCC recurrence and metastasis.
More Related Videos
13:59A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence
Published on: August 12, 2018
05:40Robust and Highly Reproducible Generation of Cortical Brain Organoids for Modelling Brain Neuronal Senescence In Vitro
Published on: May 5, 2022
Related Concept Videos
02:18Interference and Diffraction
01:23RNA Interference
This process occurs naturally in cells, often through the activity of genomically-encoded microRNAs. Researchers can take advantage of this mechanism by introducing synthetic RNAs to deactivate specific genes for research or therapeutic purposes. For example, RNAi could be used...
02:15Replicative Cell Senescence
01:37Energy to Drive Translocation
Generally, polypeptides are unfolded by two distinct...
01:16Interference and Decay
Interference occurs when competing memories hinder the retrieval of particular information. It can be classified into two types: proactive and retroactive interference. Proactive...
01:10Interference: Path Lengths
Two special sources may be considered when they are in phase. This can be easily achieved by feeding the two sources from the same source. An example would be synchronizing the two speakers by feeding them with the same source, such as the sound waves produced by a tuning fork. This setup ensures that the two sources have the same frequency and are...