Abstract 3167: Loss of HP1α alters the integrity of the nuclear lamina, thereby promoting invasion

Abstract

Abstract Malignant cell invasion is accompanied by complex changes in nuclear morphology and chromatin patterning that have been utilized by pathologists to determine malignancy. Members of the HP1 family modulate chromatin plasticity, with the HP1α paralog required to maintain the condensation of transcriptionally silent heterochromatin and to sequester it at the nuclear periphery. While increased expression of HP1α is proposed to aid the onset of malignancy, the acquisition of an invasive phenotype correlates with the loss of this architectural protein in many solid tumors including those of the thyroid, kidney, colon and breast. We have shown in a Drosophila model of epithelial cell invasion that loss of HP1α synergistically enhances invasion in cells with an activated oncogenic pathway. In the poorly invasive MCF7 breast cells, loss of HP1α increases their invasive potential and promotes epithelial plasticity. These phenotypic changes are associated altered nuclear morphology including increased nuclear grooves and indentations, diffuse chromatin patterning and a loss of heterochromatin at the nuclear periphery. Since during metastatic invasion, the nucleus, the largest and most rigid cellular of organelle, becomes malleable enough to squeeze through interstitial spaces in the surrounding tissue. This lead us to propose that loss of HP1α causes a remodelling of nuclear periphery thereby increasing nuclear malleability. Here we demonstrate that HP1α knockdown in MCF7 cells decreases mechanical stability of the nuclei and altering the integrity of nuclear lamina. While total levels of Lamin A/C, Lamin B1 and Lamin B2 are unchanged within the cell, their solubility and thus localization within the nucleus is altered. We also demonstrate how this change in the lamina effects other proteins that function at the nuclear periphery. Together, these findings suggest that when loss of HP1α increases invasive potential there is a corresponding disruption to the nuclear periphery, creating a weakness in these cells that could be exploited for therapeutic benefit. Citation Format: Tracy K. Hale, Raoul Solomon. Loss of HP1α alters the integrity of the nuclear lamina, thereby promoting invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3167.