SIAH1, a regulator of the Wnt/[beta]-catenin pathway in human adrenocortical cells

Pierre Puygrenier; Karine Perlemoine; Bruno Ragazzon; Anne Jouinot; Constantine Stratakis; Jerome Bertherat; Annabel Berthon

doi:10.1530/endoabs.99.P235

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Endocrine Abstracts (2024) 99 P235 | DOI: 10.1530/endoabs.99.P235

ECE2024 Poster Presentations Adrenal and Cardiovascular Endocrinology (95 abstracts)

SIAH1, a regulator of the Wnt/β-catenin pathway in human adrenocortical cells

Pierre Puygrenier ¹ , Karine Perlemoine ¹ , Bruno Ragazzon ¹ , Anne Jouinot ¹ , Constantine Stratakis ^2,3 , Jérôme Bertherat ¹ & Annabel Berthon ¹

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¹Institut Cochin, Paris, France; ²Research Institute, ELPEN, Pikermi, Athens, Greece; ³Human Genetics & Precision Medicine, Heraklion, Greece

The most frequent molecular alteration in adrenocortical tumors (ACT) is the activation of the Wnt/β-catenin pathway that is associated with poor prognosis in adrenocortical carcinoma. Activating β-catenin mutation (p.S31, p.S37, p.S45, T.41) inhibiting its proteosomal degradation by the canonical destruction complex is responsible for its abnormal activation in roughly 30% of ACT. However, the E3 ubiquitin protein ligase 1, SIAH1 is able to ubiquitinate β-catenin even while mutated in intestinal cells, we then, investigate if SIAH1 regulates both wild-type and mutant β-catenin in H295R human adrenocortical cells. We demonstrate that SIAH1 interacts with β-catenin and increases both wild-type and mutant β-catenin ubiquitination through its catalytic RING finger domain. Overexpression of SIAH1 results then, in a decrease in β-catenin half-life (−25%) that is sufficient to reduce β-catenin transcriptional activity (−50%) measured with the TOPFlash reporter even in presence of β-catenin mutation (p.S45) in H295R cells. However, the overexpression of SIAH1 deleted from its catalytic domain does not affect neither β-catenin activity nor its ubiquitination suggesting that the effect of SIAH1 on β-catenin activity depends on its E3 ubiquitin activity. Altogether, our results suggest that SIAH1 indirectly regulates β-catenin transcriptional activity and that promoting SIAH1 activity could limit the activation of this pro-oncogenic pathway while Wnt/β-catenin signaling is constitutively activated.