NOX4 prevents the recruitment of PAX8 and NKX2.1 to chromatin in BRAF-mutated thyroid cancer cells.

Radom, M.; Buffet, C.; Cazarin, J.; Harinquet, M.; Coelho de Faria, C.; Braye, F.; Nobre, C.; Aglave, M.; Mesloub, Y.; Dayris, T.; DROIN, N.; Godefroy, K.; Bani, M.-A.; Al Ghuzlan, A.; Leboulleux, S.; Lamartina, L.; DUPUY, C.

doi:10.1101/2025.04.14.647724

bioRxiv · 10.1101/2025.04.14.647724

NOX4 prevents the recruitment of PAX8 and NKX2.1 to chromatin in BRAF-mutated thyroid cancer cells.

Radom, M.·Buffet, C.·Cazarin, J.·Harinquet, M.·Coelho de Faria, C.·Braye, F.·Nobre, C.·Aglave, M.·Mesloub, Y.·Dayris, T.·DROIN, N.·Godefroy, K.·Bani, M.-A.·Al Ghuzlan, A.·Leboulleux, S.·Lamartina, L.·DUPUY, C.

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Abstract

Radioiodine (RAI) therapy, used for treating thyroid cancers, hinges on the expression of the Sodium Iodide Symporter (NIS). The majority of differentiated thyroid cancers (DTCs) are papillary, with a BRAFV600E mutation. This mutation correlates with an absence of RAI uptake, due to low NIS expression and a low differentiation score. NADPH oxidase 4 (NOX4)-derived ROS contribute to NIS repression in BRAFV600E-mutated thyroid cancer cells. Depleting NOX4 enhances the reactivation of NIS. This reversibility implies an epigenetic mechanisms contribution. Our findings indicate that NOX4 generates oxidative DNA damage in BRAFV600E-mutated thyroid cancer cells. DNA repair proteins such as OGG1 and MSH2/MSH6 proteins, in cooperation with DNMT1, turn these damages into transcription-blocking damages. This prevents the binding of PAX8 and NKX2.1 - two key transcription factors involved in thyroid differentiation - to the chromatin. Co-inhibition of the MAPK pathway, which regulates MSH2/MSH6 and DNMT1 expressions, and the TGF-{beta}1 pathway, which regulates NOX4 expression, fortifies the recruitment of the two transcription factors to the chromatin. Collectively, our findings present a molecular basis for NOX4s role in thyroid dedifferentiation.

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Radom, M., Buffet, C., Cazarin, J., Harinquet, M., Coelho de Faria, C., Braye, F., Nobre, C., Aglave, M., Mesloub, Y., Dayris, T., DROIN, N., Godefroy, K., Bani, M.-A., Al Ghuzlan, A., Leboulleux, S., Lamartina, L., DUPUY, C.. 2025-04-21. NOX4 prevents the recruitment of PAX8 and NKX2.1 to chromatin in BRAF-mutated thyroid cancer cells.. https://doi.org/10.1101/2025.04.14.647724

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