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Release of transcriptional repression via ErbB2-induced, SUMO-directed phosphorylation of myeloid zinc finger-1 serine 27 activates lysosome redistribution and invasion
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- Brix, Ditte Marie (author)
- Danish Cancer Society
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- Tvingsholm, Siri Amanda (author)
- Danish Cancer Society
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- Hansen, Malene Bredahl (author)
- Danish Cancer Society
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- (creator_code:org_t)
- 2019-01-08
- 2019
- English.
- In: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 38:17, s. 3170-3184
- Journal article (peer-reviewed)
Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
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