RAC1 induces nuclear alterations through the LINC complex to enhance melanoma invasiveness

Abstract

RHO GTPases are key regulators of the cytoskeletal architecture, which impacts on a broad range of biological processes in malignant cells including motility, invasion and metastasis, thereby affecting tumor progression. One of the constrains during cell migration, is the diameter of the pores through which cells pass. In this respect, the size and shape of the nucleus poses a major limitation. Therefore, enhanced nuclear plasticity can promote cell migration. Nuclear morphology is determined in part through the cytoskeleton, which connects to the nucleoskeleton through the LINC complex. Here, we unravel the role of RAC1 as an orchestrator of nuclear morphology in melanoma cells. We demonstrate that activated RAC1 promotes nuclear alterations through its effector PAK1 and the tubulin cytoskeleton, thereby enhancing migration and intravasation of melanoma cells. Disruption of the LINC complex prevented RAC1-induced nuclear alterations and the invasive properties of melanoma cells. Thus, RAC1 induces nuclear morphology alterations through microtubules and the LINC complex to promote an invasive phenotype in melanoma cells. [Media: see text]

Post-Translational Modification and Subcellular Compartmentalization: Emerging Concepts on the Regulation and Physiopathological Relevance of RhoGTPases

“…Rac1-regulated actin dynamics contribute to nuclear membrane organization, which in turn can have an impact on LMNA/C-emerin complex distribution, supporting direct crosstalk between nuclear actin network changes and lamin cortex integrity and remodeling; further, Rho GTPase control of the cytoskeleton is an additional input, through the LINC complex, onto nuclear mechanoadaptation. Current investigations demonstrate that Rac1 induces nuclear alterations through microtubules and LINC complex to promote an invasive phenotype in melanoma cells [168]. Rho GTPases are also involved in the specific control of the perinuclear actin cap, a specialized cytoskeletal structure of fibers contacting the nucleus that regulates both nuclear morphology and re-orientation during front-rear polarization.…”

A comprehensive signature based on endoplasmic reticulum stress-related genes in predicting prognosis and immunotherapy response in melanoma

“…In melanoma, selective PI3Kβ inhibitors could inhibit the growth and migration of melanoma cell lines induced by mutant RAC1 43 . Colón-Bolea et al 44 found that RAC1 enhanced melanoma invasiveness by inducing nuclear alterations through the LINC complex. In our study, we validated that the suppression of the RAC1 expression indeed attenuated the proliferation and migration as well as augmented the apoptosis of melanoma cells, which was consistent with the conclusions reported in other studies.…”

LINC complex independent perinuclear actin organization and cell migration

“…Indeed, migration of cells in a LINC complex independent manner or even in a faster rate upon inhibition of the LINC complex was reported for mouse melanoma cells (Fracchia et al, 2020), human lung cancer cells (Lv et al, 2015) and rat mammary adenocarcinoma cells (Sharma et al, 2021). Still, it should be noted that there are other cancer cells that do require the LINC complex to support their migration (Colón-Bolea et al, 2020;Imaizumi et al, 2018;Infante et al, 2018). Interestingly, in parallel there are accumulating reports on down-regulation of LINC complex components in various cancer types such as breast cancer, lung cancer, prostate cancer and liver cancer (Cartwright and Karakesisoglou, 2014;Lv et al, 2015;Marmé et al, 2008;Matsumoto et al, 2015;Sharma et al, 2021;Sur-Erdem et al, 2020;Tessema et al, 2008;Yajun et al, 2017).…”