Open AccessEpigenetic reactivation of LINE ‐1 retrotransposon disrupts Nu RD corepressor functions and induces oncogenic transformation in human bronchial epithelial cells
Author(s) -
Bojang Pasano,
Ramos Kenneth S.
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12329
Subject(s) - corepressor , cancer research , gene silencing , chemistry , epigenetics , microbiology and biotechnology , carcinogen , telomerase , transactivation , retrotransposon , biology , repressor , transcription factor , gene , biochemistry , transposable element , genome
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 ( HBEC s) 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 (Nu RD ) complex. Carcinogen challenge was also associated with partial displacement of constituent proteins from the nuclear to the cytoplasmic compartment. Disruption of Nu RD 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 ATP ase‐binding domains of Mi2β. Sustained expression of L1 in HBEC s 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 Nu RD constituent proteins is a critical molecular event in the activation of L1 retrotransposon. L1 expression creates a microenvironment in HBEC s that is conducive to neoplasia and malignant transformation.