The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2+ breast cancer cells
Open Access
- 1 January 2019
- journal article
- research article
- Published by The Company of Biologists in Biology Open
- Vol. 8 (4), bio038323
- https://doi.org/10.1242/bio.038323
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.Funding Information
- Compagnia di San Paolo (2015.0323)
This publication has 45 references indexed in Scilit:
- CHD4 in the DNA-damage response and cell cycle progression: not so NuRDy nowBiochemical Society Transactions, 2013
- Trastuzumab: Updated Mechanisms of Action and Resistance in Breast CancerFrontiers in Oncology, 2012
- Heterogeneity in breast cancerJCI Insight, 2011
- Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011Annals of Oncology, 2011
- Principles and Current Strategies for Targeting Autophagy for Cancer TreatmentClinical Cancer Research, 2011
- Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasisEndocrine-Related Cancer, 2010
- Autophagy Facilitates the Development of Breast Cancer Resistance to the Anti-HER2 Monoclonal Antibody TrastuzumabPLOS ONE, 2009
- The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunitiesEuropean Journal of Cancer, 2001
- A new mathematical model for relative quantification in real-time RT-PCRNucleic Acids Research, 2001
- Molecular mechanisms underlying ErbB2/HER2 action in breast cancerOncogene, 2000