Abstract C282: The carcinogen cadmium is a HIF1A stabilizer that reduces HIF1 activity through cytosolic sequestration of HIF1A within K63-linked ubiquitinated aggregates.

Hypoxia-inducible factor-1 (HIF1) is a master transcription factor that orchestrates the adaptation of tumor cells to hypoxia by activating the expression of a broad range of genes promoting neoangiogenesis, tumor growth, glycolysis, metastasis, and resistance to treatments. Accumulating evidence now suggests that this adaptation depends on the stabilization or the increased synthesis of the HIF1A subunit. To have a better understanding of HIF1A regulation, we focused our attention on the environmental carcinogen cadmium (Cd). Our data now challenge these hypotheses and reveal unique and opposing activities of Cd on HIF1A expression and activity. Instead of a mere action on synthesis, Cd increases by itself the stability of HIF1A protein under normoxia; independently of proteasome impairment, oxidative damage or endoplasmic reticulum stress. However, little if any HIF1A is able to translocate to the nucleus of Cd-treated cells where it activates barely HIF1 transcriptional function. Consistently, Cd dominantly inhibited hypoxia-induced HIF1 activity. Interestingly, HIF1A stabilization and inhibition of activity coincided with its association with cytosolic K63-linked ubiquitinated aggregates. We therefore propose that Cd would stabilize HIF1A but the exaggerated K63 ubiquitination would foster aggregation of HIF1A with ubiquitinated proteins, thus precluding HIF1A from interacting with its downstream nuclear targets. The unique stabilization and sequestration of HIF1A we highlighted with cadmium unravels a novel regulatory mechanism of HIF1 activity. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C282. Citation Format: Abderrahman Chargui, Amine Belaid, Valerie Vouret, Michel Tauc, Jacques Pouyssegur, Michele Veronique El May, Paul Hofman, Philippe Poujeol, Baharia Mograbi. The carcinogen cadmium is a HIF1A stabilizer that reduces HIF1 activity through cytosolic sequestration of HIF1A within K63-linked ubiquitinated aggregates. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C282.