MICAL2 as a key effector of β-catenin signaling driving melanoma progression and therapeutic resistance.

Authors

Pierre Sohier, Jérémy H Raymond, Zackie Aktary, Nour Zidi, Lara Araktingi, Nisamanee Charoenchon, Céline Pisibon, Sylvie Caberia, Eric Pasmant, Nicolas Macagno, Véronique Delmas, Caroline Gaudy-Marqueste, Eirikur Steingrimsson, Robert Ballotti, Valérie Petit, Lionel Larue

Published in

Cell death and differentiation. Aug 14, 2026. Epub Aug 14, 2026.

Abstract

β-catenin plays a pivotal role in oncogenesis through its involvement in cell-cell adhesion, Wnt signaling, and transcriptional regulation. Dysregulation of β-catenin contributes to tumorigenesis by promoting proliferation, bypassing senescence, and enhancing migration and invasion. In melanoma, however, its role has been controversial, with studies reporting conflicting effects on proliferation, metastasis, and patient survival. Here, we demonstrate that activation of β-catenin is associated with a poor prognosis in melanoma. This conclusion is based on immunohistochemical analysis of a cohort of 157 patients and the identification of a genetic signature for melanoma upon β-catenin activation. This signature includes known targets such as APCDD1 and AXIN2, as well as previously unknown targets like MICAL2 and SLC1A5. Notably, MICAL2 (Molecule Interacting with CasL 2) emerged as a key regulator of the invasive phenotype, with high expression levels correlating with adverse outcomes. Functional studies confirmed that MICAL2 is transcriptionally regulated by β-catenin. Nras and Braf mouse melanoma models further validated the conserved regulation of MICAL2 by β-catenin, linking it to melanoma initiation and metastasis. Moreover, MICAL2 expression is enriched in melanoma cells resistant to BRAF inhibitors, and MICAL2 downregulation restores therapeutic sensitivity. These findings highlight MICAL2 as a central effector of β-catenin signaling and a mediator of melanoma progression and resistance. Given the therapeutic challenges of directly targeting β-catenin, inhibiting the enzymatic activity of MICAL2 offers a promising and innovative strategy to improve outcomes in β-catenin-driven melanoma.

PMID:
42601381
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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