Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark.
Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, 00014UH, Helsinki, Finland.
Oncogene. 2019 Apr;38(17):3170-3184. doi: 10.1038/s41388-018-0653-x. Epub 2019 Jan 8.
HER2/ErbB2 activation turns on transcriptional processes that induce local invasion and lead to systemic metastasis. The early transcriptional changes needed for ErbB2-induced invasion are poorly understood. Here, we link ErbB2 activation to invasion via ErbB2-induced, SUMO-directed phosphorylation of a single serine residue, S27, of the transcription factor myeloid zinc finger-1 (MZF1). Utilizing an antibody against MZF1-pS27, we show that the phosphorylation of S27 correlates significantly (p < 0.0001) with high-level expression of ErbB2 in primary invasive breast tumors. Phosphorylation of MZF1-S27 is an early response to ErbB2 activation and results in increased transcriptional activity of MZF1. It is needed for the ErbB2-induced expression of MZF1 target genes CTSB and PRKCA, and invasion of single-cells from ErbB2-expressing breast cancer spheroids. The phosphorylation of MZF1-S27 is preceded by poly-SUMOylation of K23, which can make S27 accessible to efficient phosphorylation by PAK4. Based on our results, we suggest for an activation mechanism where phosphorylation of MZF1-S27 triggers MZF1 dissociation from its transcriptional repressors such as the CCCTC-binding factor (CTCF). Our findings increase understanding of the regulation of invasive signaling in breast cancer by uncovering a detailed biological mechanism of how ErbB2 activation can rapidly lead to its invasion-promoting target gene expression and invasion.
HER2/ErbB2 的激活开启了转录过程，诱导局部浸润，并导致全身性转移。ErbB2 诱导浸润所需的早期转录变化知之甚少。在这里，我们通过 ErbB2 诱导的、SUMO 导向的转录因子髓系锌指蛋白-1（MZF1）单个丝氨酸残基 S27 的磷酸化，将 ErbB2 激活与浸润联系起来。利用针对 MZF1-pS27 的抗体，我们表明 S27 的磷酸化与原发性浸润性乳腺癌中高表达 ErbB2 显著相关（p<0.0001）。MZF1-S27 的磷酸化是 ErbB2 激活的早期反应，导致 MZF1 的转录活性增加。它是 ErbB2 诱导的 MZF1 靶基因 CTSB 和 PRKCA 的表达以及 ErbB2 表达的乳腺癌球体单细胞浸润所必需的。MZF1-S27 的磷酸化之前是 K23 的多聚 SUMO 化，这可以使 S27 易于被 PAK4 进行有效的磷酸化。基于我们的结果，我们提出了一种激活机制，其中 MZF1-S27 的磷酸化触发 MZF1 与其转录抑制剂（如 CCCTC 结合因子（CTCF））的解离。我们的发现通过揭示 ErbB2 激活如何迅速导致其促进侵袭的靶基因表达和侵袭的详细生物学机制，增加了对乳腺癌侵袭性信号转导的调控的理解。
