Increased Lamin B1 Levels Promote Cell Migration by Altering Perinuclear Actin Organization

Abstract

Cell migration requires reposition and reshaping of the cell nucleus. The nuclear lamina is highly important for migration of both primary and cancer cells. B-type lamins are important for proper migration of epicardial cells and neurons and increased lamin B to lamin A ratio accelerates cancer cell migration through confined spaces. Moreover, a positive association between lamin B1 levels and tumor formation and progression is found in various cancer types. Still, the molecular mechanism by which B-type lamins promote cell migration is not fully understood. To better understand this mechanism, we tested the effects of lamin B1 on perinuclear actin organization. Here we show that induction of melanoma cell migration leads to the formation of a cytosolic Linker of Nucleoskeleton and Cytoskeleton (LINC) complex-independent perinuclear actin rim, which has not been detected in migrating cells, yet. Significantly, increasing the levels of lamin B1 but not the levels of lamin A prevented perinuclear actin rim formation while accelerated the cellular migration rate. To interfere with the perinuclear actin rim, we generated a chimeric protein that is localized to the outer nuclear membrane and cleaves perinuclear actin filaments in a specific manner without disrupting other cytosolic actin filaments. Using this tool, we found that disruption of the perinuclear actin rim accelerated the cellular migration rate in a similar manner to lamin B1 over-expression. Taken together, our results suggest that increased lamin B1 levels can accelerate cell migration by inhibiting the association of the nuclear envelope with actin filaments that may reduce nuclear movement and deformability.

Lamin B1 Accumulation’s Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes

“…Interestingly, LMNB1-associated disorders seem to share the fact that the Lamin B1 level of expression (either increased or decreased in different disease models) is responsible for the pathological phenotype, suggesting a very close relation between a morphological, physical, and functional balance [35]. Several new evidences also suggest that Lamin B1 levels can be relevant for cell migration mechanisms, neurogenesis control, and cellular aging [37][38][39]. Stemming from these reflections, our astrocytic in vitro ADLD cellular model highlighted new molecular and functional insights that could give new clues to this biological and pathological intriguing puzzle.…”

All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System

“…A thorough search of the relevant literature did not yield any publicationsthat report a peri-nuclear force or the actin cap in cancer cells. An indirect study on melanoma cancer cells demonstrated that the actin rim (another peri-nuclear actin organization located around but not covering the nucleus) reduces cell migration rates 41 , indirectly suggesting the existence of a peri-nuclear force.…”

All-optical mechanobiology interrogation of YAP in human cancer and normal cells using a novel multi-functional system

“…We do not find any publications available that report peri-nuclear force or actin-cap in cancer cells. An indirect study on melanoma cancer cells demonstrated that the actin rim (another peri-nuclear actin organization that is located around but not covering the nucleus) reduces cell migration rates [30], indirectly suggesting the existence of peri-nuclear force. However, no direct experimental data are reported.…”

“…In cancer cells, overexpression of Lamin A facilitates the formation of actin-rim and restricts the cancer cell migration. Overexpression of Lamin B reduces the actin-rim formation and promotes migration[30]. Peri-nuclear force might be involved in this process due to the existence of peri-nuclear actin organization and the effect of Lamin A.…”