Evidence map›Paper›PMID 39301555›Full record

ArticleFrontiers in oncology2024

Targeted inhibition of BET proteins in HPV16-positive head and neck squamous cell carcinoma reveals heterogeneous transcriptional responses.

Aakarsha Rao, Milan S Stosic, Chitrasen Mohanty, Dhruthi Suresh, Albert R Wang, Denis L Lee, Kwangok P Nickel, Darshan S Chandrashekar, Randall J Kimple, Paul F Lambert and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Frontiers in oncology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors.

Aakarsha RaoDepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States.
Milan S StosicDepartment of Life Sciences and Health, Faculty of Health Sciences, OsloMet - Oslo Metropolitan University, Oslo, Norway.
Chitrasen MohantyDepartment of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, United States.
Dhruthi SureshDepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States.
Albert R WangDepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States.
Denis L LeeMcArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.
Kwangok P NickelDepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States.
Darshan S ChandrashekarMolecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States.
Randall J KimpleDepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States.
Paul F LambertMcArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.
Christina KendziorskiDepartment of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, United States.
Trine B RoungeCentre for Bioinformatics, Department of Pharmacy, University of Oslo, Oslo, Norway.
Gopal IyerDepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States.

Funding

UW COMPREHENSIVE CANCER CENTER SUPPORTP30CA014520 · NCI · UNIVERSITY OF WISCONSIN-MADISON · PI Justine Yang Bruce · 1985 to 2026
$142.6M
Project 3: Modulation of the head and neck tumor immune microenvironment by targeting the TAM family of receptorsP50CA278595 · NCI · UNIVERSITY OF WISCONSIN-MADISON · PI David J Beebe · 2022 to 2026
$12.5M
Project 4: Role of Receptor Tyrosine Kinase AXL in HNSCC Therapy ResistanceP50DE026787 · NIDCR · UNIVERSITY OF WISCONSIN-MADISON · PI HARARI, PAUL M · 2016 to 2020
$10.8M
Combining BET protein inhibitors with radiation in HPV oropharyngeal cancerR21CA267518 · NCI · UNIVERSITY OF WISCONSIN-MADISON · PI IYER, GOPAL · 2023 to 2024
$379k
NCI NIH HHS P30 CA014520NCI NIH HHS P50 CA278595NCI NIH HHS R21 CA267518NIDCR NIH HHS P50 DE026787
6 · The paper itself

Abstract

Human papillomaviruses (HPV), most commonly HPV16, are associated with a subset of head and neck squamous cell carcinoma (HNSCC) tumors, primarily oropharyngeal carcinomas, with integration of viral genomes into host chromosomes associated with worse survival outcomes. We analyzed TCGA data and found that HPV+ HNSCC expressed higher transcript levels of the bromodomain and extra terminal domain (BET) family of transcriptional coregulators. The role of BET protein-mediated transcription of viral-cellular genes in the viral-HNSCC genomes needs to be better understood. Using a combination of TAME-Seq, qRT-PCR, and immunoblot analyses, we show that BET inhibition downregulates E6 and E7 significantly, with heterogeneity in the downregulation of viral transcription across different HPV+ HNSCC cell lines. Chemical BET inhibition was phenocopied with the knockdown of BRD4, mirroring the downregulation of viral E6 and E7 expression. We found that BET inhibition directly downregulated c-Myc and E2F expression and induced CDKN1A (p21) expression, leading to a G1-cell cycle arrest with apoptotic activity. Overall, our studies demonstrate that BET inhibition regulates both E6 and E7 viral and key cellular cell cycle regulator E2F gene expression and cellular gene expression in HPV-associated HNSCC and highlight the potential of BET inhibitors as a therapeutic strategy for this disease while also underscoring the importance of considering the heterogeneity in cellular responses to BET inhibition.

Indexed as

BRD4E6E7HNSCCHPV16RNA-seq

Identifiers

PMID39301555
PMCPMC11410754

What OpenQuestion holds

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.