A requirement for dimerization of HP1Hsα in suppression of breast cancer invasion

Laura E. Norwood, Timothy J. Moss, Naira V. Margaryan, Sara L. Cook, Lindsay Wright, Elisabeth A. Seftor, Mary J.C. Hendrix, Dawn A. Kirschmann, Lori L. Wallrath

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39 Scopus citations

Abstract

The development and progression of cancer is controlled by gene expression, often regulated through chromatin packaging. Heterochromatin protein 1 Hsα (HP1Hsα), one of three human HP1 family members, participates in heterochromatin formation and gene regulation. HP1 Hsα possesses an amino-terminal chromodomain, which binds methylated lysine 9 of histone H3 (meK9 H3), and a carboxyl-terminal chromoshadow domain (CSD) that is required for dimerization and interaction with partner proteins. HP1Hsα is down-regulated in invasive metastatic breast cancer cells compared with poorly invasive nonmetastatic breast cancer cells. Expression of EGFP-HP1Hsα in highly invasive MDA-MB-231 cells causes a reduction in in vitro invasion, without affecting cell growth. Conversely, knock-down of HP1Hsα levels in the poorly invasive breast cancer cell line MCF-7 increased invasion, without affecting cell growth. To determine whether functions of the CSD were required for the regulation of invasion, mutant forms of HP1Hsα were expressed in MDA-MB-231 cells. AW174A mutation that disrupts interactions between HP1Hsα and PXVXL-containing partner proteins reduced invasion similar to that of the wild type protein. In contrast, an I165E mutation that disrupts dimerization of HP1Hsα did not decrease invasion. No gross changes in localization and abundance of HP1 Hsβ, HP1Hsγ, and meK9 H3 were observed upon expression of wild type and mutant forms of HP1Hsα in MDA-MB-231 cells. Taken together, these data demonstrate that modulation of HP1Hsα alters the invasive potential of breast cancer cells through mechanisms requiring HP1 dimerization, but not interactions with PXVXL-containing proteins.

Original languageEnglish (US)
Pages (from-to)18668-18676
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number27
DOIs
StatePublished - Jul 7 2006

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    Norwood, L. E., Moss, T. J., Margaryan, N. V., Cook, S. L., Wright, L., Seftor, E. A., Hendrix, M. J. C., Kirschmann, D. A., & Wallrath, L. L. (2006). A requirement for dimerization of HP1Hsα in suppression of breast cancer invasion. Journal of Biological Chemistry, 281(27), 18668-18676. https://doi.org/10.1074/jbc.M512454200