2. Academic Validation
  3. NOX4-derived oxidative DNA damage impairs thyroid differentiation through an epigenetic mechanism in BRAF-mutated radioactive iodine refractory papillary thyroid cancer cells

NOX4-derived oxidative DNA damage impairs thyroid differentiation through an epigenetic mechanism in BRAF-mutated radioactive iodine refractory papillary thyroid cancer cells

  • Int J Biol Sci. 2026 Jan 15;22(4):1674-1692. doi: 10.7150/ijbs.123980.
Mickaëlle Radom 1,  Camille Buffet 2,  Juliana Cazarin 1 3,  Marylin Harinquet 1,  Caroline Coelho de Faria 1,  Floriane Brayé 4,  Catline Nobre 4,  Marine Aglave 5,  Yasmina Mesloub 5,  Thibault Dayris 5,  Nathalie Droin 6,  Karine Godefroy 7,  Mohamed-Amine Bani 7,  Abir Al Ghuzlan 1 7,  Sophie Leboulleux 8,  Livia Lamartina 9,  Corinne Dupuy 1
Affiliations

Affiliations

  • 1 UMR 9019 CNRS, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • 2 Sorbonne Université, Service de Pathologies Thyroïdiennes et Tumeurs endocrines, Groupe de Recherche Clinique n°16 Tumeurs Thyroïdiennes, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
  • 3 Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21941-170, RJ, Brazil.
  • 4 INSERM U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • 5 Bioinformatics Plateform, Gustave Roussy, Villejuif, France.
  • 6 AMMICa Platform, INSERM US23, CNRS UAR 3655, Gustave Roussy, Villejuif, France.
  • 7 Cancer Medical Pathology and Biology Department, Gustave Roussy, Villejuif, France.
  • 8 Department of Endocrinology and Diabetology, Hôpitaux Universitaires de Genève, Geneve, Switzerland.
  • 9 Cancer Medicine Department, Gustave Roussy, Université Paris Saclay, Villejuif, France.
PMID: 41694580 DOI: 10.7150/ijbs.123980
Abstract

Radioiodine (RAI) therapy, used for treating differentiated thyroid cancers (DTCs), hinges on the functional expression of the sodium-iodide symporter (NIS). However, up to 60% of papillary thyroid carcinomas, the most common DTC subtype, harbor BRAFV600E mutations, which are strongly associated with reduced NIS expression, impaired RAI uptake, and poor differentiation scores. For patients with RAI-refractory, a promising therapeutic strategy is to restore RAI sensitivity by inducing tumor redifferentiation. Here, we demonstrate that NOX4-derived Reactive Oxygen Species (ROS) contribute to NIS repression in BRAFV600E-mutated thyroid Cancer cells. Particularly, NOX4-generated oxidative DNA damage recruits DNA repair proteins, including OGG1 and MSH2/MSH6 proteins, which in cooperation with DNMT1, convert these lesions into transcription-blocking events. This mechanism prevents key thyroid differentiation transcription factors, PAX8 and NKX2.1, from accessing their chromatin binding sites, thereby silencing NIS expression. Importantly, combining inhibition of the MAPK pathway, which regulates MSH2/MSH6 and DNMT1 expression, and the TGF-β1 pathway, which controls NOX4 expression, restores PAX8 and NKX2.1 chromatin occupancy. Compared to normal tissue an increased expression of NOX4, OGG1, MSH2/MSH6 proteins and phospho-Smad3 was found in RAI Refractory BRAFV600E mutated tumors. Collectively, our findings reveal a mechanistic basis for NOX4's role in thyroid dedifferentiation.

Keywords

BRAFV600E; NADPH oxidase; Oxidative DNA damage; ROS; Radioiodine refractory thyroid cancer..

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