The High Mobility Group A1 (HMGA1) Chromatin Architectural Factor Modulates Nuclear Stiffness in Breast Cancer Cells.

Beatrice Senigagliesi,Riccardo Maraspini,Enrico Pobega,Silvia Pegoraro,Hernan Morales-Navarrete,Elena Ambrosetti,Guidalberto Manfioletti,Sara Petrosino,Luisa Ulloa Severino,Riccardo Sgarra,Carlotta Penzo,Loredana Casalis,Pietro Parisse

doi:10.3390/ijms20112733

Abstract

Plasticity is an essential condition for cancer cells to invade surrounding tissues. The nucleus is the most rigid cellular organelle and it undergoes substantial deformations to get through environmental constrictions. Nuclear stiffness mostly depends on the nuclear lamina and chromatin, which in turn might be affected by nuclear architectural proteins. Among these is the HMGA1 (High Mobility Group A1) protein, a factor that plays a causal role in neoplastic transformation and that is able to disentangle heterochromatic domains by H1 displacement. Here we made use of atomic force microscopy to analyze the stiffness of breast cancer cellular models in which we modulated HMGA1 expression to investigate its role in regulating nuclear plasticity. Since histone H1 is the main modulator of chromatin structure and HMGA1 is a well-established histone H1 competitor, we correlated HMGA1 expression and cellular stiffness with histone H1 expression level, post-translational modifications, and nuclear distribution. Our results showed that HMGA1 expression level correlates with nuclear stiffness, is associated to histone H1 phosphorylation status, and alters both histone H1 chromatin distribution and expression. These data suggest that HMGA1 might promote chromatin relaxation through a histone H1-mediated mechanism strongly impacting on the invasiveness of cancer cells.

Highlights

Despite great progresses achieved in the understanding of cancer biology, metastases are still synonymous of terminal illness in several cancer types [1]
Our data highlighted a direct link between HMGA1 expression levels, cellular stiffness, and histone H1 phosphorylation, nanoscale localization, and expression levels
(1) HMGA1 and histone H1 are DNA-binding competitors [13,40]; (2) HMGA1 and histone H1 exert opposite effects: HMGA1 contributes to chromatin decondensation whereas histone H1 is involved in chromatin compaction [13]; (3) HMGA1 regulates the expression of factors involved in histone H1 phosphorylation

Summary

Introduction

Despite great progresses achieved in the understanding of cancer biology, metastases are still synonymous of terminal illness in several cancer types [1]. The nuclear lamina is a filamentous meshwork of lamin proteins juxtaposed to the inner membrane of the nuclear envelope that provides nuclear shape, supports its structure and contributes to organize the chromatin into distinct functional domains [7]. Non-histone proteins contribute to nuclear sturdiness influencing chromatin compaction state. Despite distinct families differing in functions and structural domains, all HMG proteins lack any obvious specificity for DNA consensus sequences and compete with different mechanisms with histone H1 for DNA binding, negatively influencing the formation of higher order chromatin structures [13]. We provide evidences that in breast cancer cells HMGA1 affects nuclear stiffness and that this effect could be, at least in part, explained through a mechanism involving histone H1, a protein linked to higher-order chromatin compaction. This work suggests that HMGA1 could exert its oncogenic activities by modulating the biophysical properties of cells

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Conclusion