Abstract
ABSTRACTThe 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.
Highlights
Breast cancer (BC) is considered a collection of diseases showing heterogeneity at molecular, histopathological and clinical level, which generates variable clinical courses and responses to treatments (Polyak, 2011)
chromodomain helicase DNA-binding 4 (CHD4) regulates ERBB2+ BC cell growth As the helicase CHD4 is implicated in the development of murine ERBB2+ BC (D’Alesio et al, 2016) we wanted to establish its role in a human ERBB2+ BC cell model
CHD4 depletion inhibits ERBB2 signaling pathway As ERBB2+ BC cells heavily depend on ERBB2 receptor signaling for their growth and survival, and because CHD4 depletion inhibits BC tumor development in the MMTV/NeuT model, we hypothesized that CHD4 silencing might impair the ERBB2 signaling pathway
Summary
Breast cancer (BC) is considered a collection of diseases showing heterogeneity at molecular, histopathological and clinical level, which generates variable clinical courses and responses to treatments (Polyak, 2011). The genetic and molecular characterization of breast tumors has allowed the identification of five main subtypes according to the receptor status (estrogen, progesterone or ERBB2) (Goldhirsch et al, 2011). Several malignancies are associated with mutations or increased expression of members of the EGFR family, including lung, breast, stomach, colorectal, head and neck, thyroid, pancreatic carcinomas and glioblastoma (Yarden, 2001b; Li et al, 2018; Minuto et al, 2018; Sigismund et al, 2018; von Achenbach et al, 2018; Rodríguez-Antona et al, 2010). The ERBB receptors work as homo- or heterodimers able to engage different downstream signaling modules, such as Ras/Raf/MAPK and phosphatidylinositol 3-kinase (PI3K)/ AKT pathways (Harari and Yarden, 2000; Carmona et al, 2016; Bagnato et al, 2017). ERBB2 overexpression correlates with increased progression through the cell cycle by affecting CDKN1A/p21WAF1 and CDKN1B/p27KIP1 (Carmona et al, 2016)
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