ETD

• meccanotrasduzione
• mechanotransduction
• mical
• nuclear envelope

MICAL2, a FAD-dependent monooxygenase, promotes F-actin remodeling and metastatic progression in solid tumors. While its cytoplasmic role in redox-dependent cytoskeletal regulation is established, emerging evidence suggests broader nuclear functions. Preliminary data obtained in renal adenocarcinoma cell line (786-O) indicated that MICAL2 knockdown (MIC2-KD) leads to altered nuclear morphology and increased micronuclei, suggesting impaired nuclear mechanics and nuclear fragility. Similar results were obtained in this study with several cell types, both for morphological findings and the other nuclear shape parameters. Building on these observations, we explored the new role of MICAL2 in maintaining nuclear envelope (NE) architecture and mechanosensitive behavior in tumor cells. In all cell lines, MICAL2 depletion caused consistent downregulation of LMNA/C, LMNB1, and LMNB2, along with disorganization of the LINC complex protein NESPRIN-2. These alterations coincided with nuclear defects and loss of ATM activation in response to DNA damage, indicating compromised genome surveillance. To assess MICAL2 role in extracellular mechanosensing, we cultured different cell lines on substrates of varying rigidity and microstructure (glass, plastic, soft gels, and micro-engineered “niche”) and observed that MICAL2 expression was dynamically regulated by the physical properties of the environment, confirming its mechano-responsive nature. Interestingly, only MIC2-KD cells developed primary cilia, pointing to a shift toward a quiescent, mechanically detached state. This was accompanied by transcriptional downregulation of key components of the Sonic Hedgehog and Wnt pathways, indicating impaired transduction of environmental cues. Finally, given that downregulation of Lamin A/C (LMNA) disrupts nuclear integrity and consequently alters autophagy pathways, we further investigated whether MICAL2 might influence nuclear autophagic processes. Immunofluorescence analysis of LC3B revealed that MIC2-KD in 786-O cells triggered a redistribution of LC3B between the cytoplasm and nucleus, suggesting altered autophagic dynamics at the nuclear level. Altogether, our data identify MICAL2 as a critical integrator of redox signaling, nuclear lamina stability, and mechanotransduction. Its loss destabilizes nuclear structure, uncouples mechanical inputs from transcriptional responses, and impairs genome integrity—positioning MICAL2 as a potential target in the control of tumor plasticity and progression.