Epigenetic reactivation of LINE-1 retrotransposon disrupts NuRD corepressor functions and induces oncogenic transformation in human bronchial epithelial cells

Molecular Oncology
Pasano Bojang, Kenneth S Ramos

Abstract

Long interspersed nuclear element-1 (LINE-1 or L1) reactivation is linked to poor prognosis in non-small-cell lung carcinoma (NSCLC), but the molecular bases of this response remain largely unknown. In this report, we show that challenge of human bronchial epithelial cells (HBECs) with the lung carcinogen, benzo(a)pyrene (BaP), shifted the L1 promoter from a heterochromatic to euchromatic state through disassembly of the nucleosomal and remodeling deacetylase (NuRD) complex. Carcinogen challenge was also associated with partial displacement of constituent proteins from the nuclear to the cytoplasmic compartment. Disruption of NuRD corepression by genetic ablation or carcinogen treatment correlated with accumulation of L1 mRNA and proteins. Mi2β bound directly to the L1 promoter to effect retroelement silencing, and this response required the DNA- and ATPase-binding domains of Mi2β. Sustained expression of L1 in HBECs was tumorigenic in a human-SCID mouse xenograft model, giving rise to tumors that regressed over time. Together, these results show that functional modulation of the NuRD constituent proteins is a critical molecular event in the activation of L1 retrotransposon. L1 expression creates a microenvironment in HBECs tha...Continue Reading

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Citations

Mar 15, 2019·Experimental Biology and Medicine·Kenneth S RamosIrma N Ramos
Mar 8, 2020·Environmental and Molecular Mutagenesis·Brunella Del Re, Gianfranco Giorgi
Nov 30, 2019·ERJ Open Research·Stefano GuerraKenneth S Ramos
Jul 27, 2021·Experimental Biology and Medicine·Kenneth S RamosEmma Bowers

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Methods Mentioned

BETA
deamination
xenograft
PCR
acetylation
immunoprecipitation assay
transfection
xenografts
Ch
ChIP
electrophoresis

Software Mentioned

Cytation
imagej

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