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SIRT2 Inhibition by AGK2 Promotes Perinuclear Cytoskeletal Organisation and Reduces Invasiveness of MDA-MB-231 Triple-Negative Breast Cancer Cells in Confined In Vitro Models

Lookup NU author(s): Dr Natalie Young, Professor Boguslaw ObaraORCiD, Dr Iakowos Karakesisoglou

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2024 by the authors. Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterised by the absence of targetable hormone receptors and increased metastatic rates. As nuclear softening strongly contributes to TNBC’s enhanced metastatic capacity, increasing the nuclear stiffness of TNBC cells may present a promising therapeutic avenue. Previous evidence has demonstrated the ability of Sirtuin 2 (SIRT2) inhibition to induce cytoskeletal reorganisation, a key factor in regulating nuclear mechanics. Thus, our study aimed to investigate the effect of SIRT2 inhibition on the nuclear mechanics and migratory behaviour of TNBC cells. To achieve this, SIRT2 was pharmacologically inhibited in MDA-MB-231 cells using AGK2, a SIRT2-specific inhibitor. Although SIRT2 inhibition had no effect on LINC complex composition, the AGK2-treated MDA-MB-231 cells displayed more prominent perinuclear organisations of acetylated α-tubulin, vimentin, and F-actin. Additionally, the nuclei of the AGK2-treated MDA-MB-231 cells exhibited greater resistance to collapse under osmotic shock. Scratch-wound assays also revealed that SIRT2 inhibition led to polarity defects in the MDA-MB-231 cells, while in vitro space-restrictive invasion assays highlighted their reduced migratory capacity upon AGK2 treatment. Taken together, our findings suggest that SIRT2 inhibition promotes a perinuclear cytoskeletal organisation in MDA-MB-231 cells, which enhances their nuclear rigidity and impedes their invasion through confined spaces in vitro.

Publication metadata

Author(s): Jessop E, Young N, Garcia-Del-Valle B, Crusher JT, Obara B, Karakesisoglou I

Publication type: Article

Publication status: Published

Journal: Cells

Year: 2024

Volume: 13

Issue: 23

Online publication date: 07/12/2024

Acceptance date: 05/12/2024

Date deposited: 20/12/2024

ISSN (electronic): 2073-4409

Publisher: MDPI

URL: https://doi.org/10.3390/cells13232023

DOI: 10.3390/cells13232023

Data Access Statement: The raw data supporting the conclusions of this article will be made available by the authors on request.

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