# Reduced LOXL3 Expression Disrupts Microtubule Acetylation and Drives TP53-Dependent Cell Fate in Glioblastoma

## TL;DR

Reducing LOXL3 disrupts microtubules and causes cell death in glioblastoma cells with normal TP53, but leads to cell aging in those with mutated TP53.

## Contribution

LOXL3 is identified as a key regulator of microtubule stability and cell fate in glioblastoma, with outcomes dependent on TP53 status.

## Key findings

- Reduced LOXL3 expression lowers α-tubulin acetylation and disrupts cell cycle progression.
- TP53 status determines whether LOXL3 knockdown causes apoptosis or senescence.
- LOXL3 reduction impairs adhesion and migration in TP53 wild-type glioblastoma cells.

## Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor, marked by molecular heterogeneity and poor clinical prognosis. Lysyl oxidase-like 3 (LOXL3) is frequently upregulated in GBM, but its mechanistic contribution remains insufficiently defined. Here, we investigated the functional role of LOXL3 in GBM using CRISPR-Cas9-mediated LOXL3 knockdown in two genetically distinct GBM cell lines: U87MG (wild-type TP53) and U251 (mutant TP53). Reduced LOXL3 expression markedly reduced α-tubulin acetylation, particularly in U87MG cells, and downregulated genes involved in cell cycle progression and proliferation. Both cell lines exhibited mitotic defects, including delayed cell cycle progression and spindle abnormalities; however, cell fate diverged according to TP53 status. U87MG cells, sustained spindle checkpoint activation triggered a p53-dependent spindle checkpoint response culminating in apoptosis, while U251 cells underwent mitotic slippage and senescence. Transcriptomic analyses confirmed differential regulation of apoptosis versus senescence pathways in accordance with TP53 functionality. Additionally, reduced LOXL3 expression markedly impaired adhesion and migration in U87MG cells, whereas U251 cells were minimally affected, consistent with more pronounced microtubule destabilization. Collectively, these findings identify that LOXL3 is a key regulator of microtubule homeostasis, mitotic fidelity, adhesion, and invasive behavior in GBM. Targeting LOXL3 may therefore provide a therapeutic opportunity for genotype-informed intervention in GBM.