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首页> 外文期刊>Biology Open >The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2+ breast cancer cells
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The chromodomain helicase CHD4 regulates ERBB2 signaling pathway and autophagy in ERBB2+ breast cancer cells

机译：色域解旋酶CHD4调节ERBB2 +乳腺癌细胞中的ERBB2信号通路和自噬

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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 p27KIP1upregulation, Tyr1248ERBB2 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 proliferationin 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.
机译：染色体域解旋酶DNA结合4（CHD4），核小体重构和去乙酰化酶（NuRD）复合体的成员，已被确定为调节乳腺癌（BC）增殖和迁移的致癌基因。 ERBB2是不列颠哥伦比亚省20％至30％的致癌驱动因子，其过表达导致化学抗性增加。在这里，我们调查了CHD4耗竭是否影响ERBB2级联和自噬，这代表了对治疗性抗ERBB2抗体曲妥珠单抗（Tz）的耐药机制。我们显示，CHD4在两个ERBB2 + BC细胞系中的耗竭强烈抑制细胞增殖，诱导p27KIP1上调，Tyr1248ERBB2磷酸化，ERK1 / 2和AKT去磷酸化以及ERBB2和PI3K水平下调。此外，CHD4沉默会损害自噬的后期阶段，导致LC3 II和SQSTM1 / p62水平升高，溶酶体增大和自溶酶体（ALs）积累。重要的是，我们表明CHD4耗竭和Tz的伴随治疗在体外可防止细胞增殖。我们的结果表明，CHD4在调节细胞增殖，ERBB2信号级联和自噬中起关键作用，并为将CHD4作为治疗ERBB2 + BC的潜在靶标提供了新见解。

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