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Aug 28, 2024;13 (17):

Unraveling the Role of Bromodomain and Extra-Terminal Proteins in Human Uterine Leiomyosarcoma.

Qiwei Yang, Ali Falahati, Azad Khosh, Ricardo R Lastra, Thomas G Boyer, Ayman Al-Hendy
Author Information
  1. Qiwei Yang: Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA. ORCID
  2. Ali Falahati: Poundbury Cancer Institute for Personalised Medicine, Dorchester DT1 3BJ, UK.
  3. Azad Khosh: Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. ORCID
  4. Ricardo R Lastra: Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
  5. Thomas G Boyer: Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  6. Ayman Al-Hendy: Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA. ORCID
PMID: 39273015 DOI: 10.3390/cells13171443

Abstract

Uterine leiomyosarcoma (uLMS) is the most common type of uterine sarcoma, associated with poor prognosis, high rates of recurrence, and metastasis. Currently, the molecular mechanism of the origin and development of uLMS is limited. Bromodomain and extra-terminal (BET) proteins are involved in both physiological and pathological events. However, the role of BET proteins in the pathogenesis of uLMS is unknown. Here, we show for the first time that BET protein family members, BRD2, BRD3, and BRD4, are aberrantly overexpressed in uLMS tissues compared to the myometrium, with a significant change by histochemical scoring assessment. Furthermore, inhibiting BET proteins with their small, potent inhibitors (JQ1 and I-BET 762) significantly inhibited the uLMS proliferation dose-dependently via cell cycle arrest. Notably, RNA-sequencing analysis revealed that the inhibition of BET proteins with JQ1 and I-BET 762 altered several critical pathways, including the hedgehog pathway, EMT, and transcription factor-driven pathways in uLMS. In addition, the targeted inhibition of BET proteins altered several other epigenetic regulators, including DNA methylases, histone modification, and mA regulators. The connections between BET proteins and crucial biological pathways provide a fundamental structure to better understand uterine diseases, particularly uLMS pathogenesis. Accordingly, targeting the vulnerable epigenome may provide an additional regulatory mechanism for uterine cancer treatment.

Keywords

EMT I-BET 762 JQ1 bromodomain and extra-terminal protein epigenome hedgehog pathway m6A regulators transcriptional factors transcriptome analysis uterine leiomyosarcoma

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Grants

  1. R01 HD106285/NICHD NIH HHS
  2. R01 HD106285/NIH HHS

MeSH Term

Humans
Female
Leiomyosarcoma
Uterine Neoplasms
Transcription Factors
Cell Proliferation
Azepines
Gene Expression Regulation, Neoplastic
Triazoles
Cell Cycle Proteins
Cell Line, Tumor
Epigenesis, Genetic
Cell Cycle Checkpoints
Middle Aged
Bromodomain Containing Proteins
Benzodiazepines
Proteins

Chemicals

Transcription Factors
Azepines
bromodomain and extra-terminal domain protein, human
Triazoles
(+)-JQ1 compound
molibresib
Cell Cycle Proteins
Bromodomain Containing Proteins
Benzodiazepines
Proteins
Journal Article
Article has an altmetric score of 1

Word Cloud

Created with Highcharts 10.0.0uLMSBETproteinsuterineJQ1I-BET762pathwaysregulatorsUterineleiomyosarcomamechanismBromodomainextra-terminalpathogenesisproteinanalysisinhibitionalteredseveralincludinghedgehogpathwayEMTprovideepigenomecommontypesarcomaassociatedpoorprognosishighratesrecurrencemetastasisCurrentlymolecularorigindevelopmentlimitedinvolvedphysiologicalpathologicaleventsHoweverroleunknownshowfirsttimefamilymembersBRD2BRD3BRD4aberrantlyoverexpressedtissuescomparedmyometriumsignificantchangehistochemicalscoringassessmentFurthermoreinhibitingsmallpotentinhibitorssignificantlyinhibitedproliferationdose-dependentlyviacellcyclearrestNotablyRNA-sequencingrevealedcriticaltranscriptionfactor-drivenadditiontargetedepigeneticDNAmethylaseshistonemodificationmAconnectionscrucialbiologicalfundamentalstructurebetterunderstanddiseasesparticularlyAccordinglytargetingvulnerablemayadditionalregulatorycancertreatmentUnravelingRoleExtra-TerminalProteinsHumanLeiomyosarcomabromodomainm6Atranscriptionalfactorstranscriptome

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