EGFR-19del nuclear translocation increases HDAC7 expression inhibiting the Hippo pathway and exacerbating TKI resistance in lung adenocarcinoma.
Epidermal growth factor receptor (EGFR) "membrane-cytoplasmic-nuclear translocation" occurs in EGFR-19del lung adenocarcinoma (LUAD) following resistance to tyrosine kinase inhibitors (TKIs). This study aimed to elucidate the mechanism of TKI resistance conferred by nuclear EGFR-19del.
RNA sequencing and immunohistochemistry were performed to assess histone deacetylase 7 (HDAC7) expression in LUAD with TKI resistance. Functional assays were performed both in vitro and in vivo to assess the effects of changes in HDAC7 expression on the malignant phenotype of LUAD cells and drug sensitivity to TKIs. Mass spectrometry and dual-luciferase assays were performed to verify the effect of changes in HDAC7 expression on the Hippo pathway. Chromatin immunoprecipitation and coimmunoprecipitation assays were conducted to clarify the potential role of EGFR-19del in the cell nucleus.
EGFR-19del nuclear translocation correlated with elevated HDAC7 expression in TKI-resistant cells. HDAC7 overexpression promoted malignancy and reduced TKI sensitivity, whereas HDAC7 knockdown or TSA treatment suppressed tumour growth and enhanced TKI sensitivity in vivo. Mechanistically, HDAC7 interacts with large tumour suppressor kinase 1 (LATS1) and promotes its deacetylation at K688, which reduced T1079 phosphorylation, thereby inhibiting the Hippo pathway. Concurrently, nuclear EGFR-19del acts as a coactivator to accelerate HDAC7 transcription through signal transducer and activator of transcription 3 (STAT3).
We elucidated the underlying mechanism by which nuclear EGFR-19del inhibits the Hippo pathway; these results indicate that TKIs and HDAC inhibitors may serve as a potential therapeutic strategy to reduce drug resistance in LUAD with EGFR-19del.
RNA sequencing and immunohistochemistry were performed to assess histone deacetylase 7 (HDAC7) expression in LUAD with TKI resistance. Functional assays were performed both in vitro and in vivo to assess the effects of changes in HDAC7 expression on the malignant phenotype of LUAD cells and drug sensitivity to TKIs. Mass spectrometry and dual-luciferase assays were performed to verify the effect of changes in HDAC7 expression on the Hippo pathway. Chromatin immunoprecipitation and coimmunoprecipitation assays were conducted to clarify the potential role of EGFR-19del in the cell nucleus.
EGFR-19del nuclear translocation correlated with elevated HDAC7 expression in TKI-resistant cells. HDAC7 overexpression promoted malignancy and reduced TKI sensitivity, whereas HDAC7 knockdown or TSA treatment suppressed tumour growth and enhanced TKI sensitivity in vivo. Mechanistically, HDAC7 interacts with large tumour suppressor kinase 1 (LATS1) and promotes its deacetylation at K688, which reduced T1079 phosphorylation, thereby inhibiting the Hippo pathway. Concurrently, nuclear EGFR-19del acts as a coactivator to accelerate HDAC7 transcription through signal transducer and activator of transcription 3 (STAT3).
We elucidated the underlying mechanism by which nuclear EGFR-19del inhibits the Hippo pathway; these results indicate that TKIs and HDAC inhibitors may serve as a potential therapeutic strategy to reduce drug resistance in LUAD with EGFR-19del.