The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2+ breast cancer cells

Carolina D'Alesio, Grazia Bellese, Maria Cristina Gagliani, Anastasia Lechiara, Martina Dameri, Elena Grasselli, Luisa Lanfrancone, Katia Cortese, Patrizio Castagnola

Research output: Contribution to journalArticle

Abstract

The chromodomain helicase DNA-binding 4 (CHD4), a member of the nucleosome remodeling and deacetylases (NuRD) complex, has been identified as an oncogene that modulates proliferation and migration of breast cancers (BC). ERBB2 is an oncogenic driver in 20-30% of BC in which its overexpression leads to increased chemoresistance. Here we investigated whether CHD4 depletion affects the ERBB2 cascade and autophagy, which represents a mechanism of resistance against Trastuzumab (Tz), a therapeutic anti-ERBB2 antibody. We show that CHD4 depletion in two ERBB2+ BC cell lines strongly inhibits cell proliferation, induces p27KIP1 upregulation, Tyr1248 ERBB2 phosphorylation, ERK1/2 and AKT dephosphorylation, and downregulation of both ERBB2 and PI3K levels. Moreover, CHD4 silencing impairs late stages of autophagy, resulting in increased levels of LC3 II and SQSTM1/p62, lysosomal enlargement and accumulation of autolysosomes (ALs). Importantly, we show that CHD4 depletion and concomitant treatment with Tz prevent cell proliferation in vitro. Our results suggest that CHD4 plays a critical role in modulating cell proliferation, ERBB2 signaling cascade and autophagy and provide new insights on CHD4 as a potential target for the treatment of ERBB2+ BC.

Original languageEnglish
Article numberbio038323
JournalBiology Open
Volume8
Issue number4
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • Autophagy
  • Breast cancer
  • CHD4
  • ERBB2
  • Trastuzumab

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    D'Alesio, C., Bellese, G., Gagliani, M. C., Lechiara, A., Dameri, M., Grasselli, E., Lanfrancone, L., Cortese, K., & Castagnola, P. (2019). The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2+ breast cancer cells. Biology Open, 8(4), [bio038323]. https://doi.org/10.1242/bio.038323