Ten Eleven Translocation 1（TET1）的经典氧化酶活性和其肿瘤抑制作用广为人知。我们发现在常见缺氧性实体肿瘤中，高TET1的表达与患者的生存率下降有关，这与其肿瘤抑制作用不一致。通过一系列体外和体内研究，以甲状腺癌为模型，我们证明TET1在正氧和意外的低氧环境下都有肿瘤抑制功能。机制上，TET1通过作为HIF1α的共同激活剂，在低氧状态下调节CK2B转录，介导HIF1α-p300的相互作用，这与其酶活性无关。CK2激活AKT / GSK3β信号通路促进肿瘤形成。激活的AKT / GSK3β信号通路通过阻止HIF1α的K48-联结泛素化和降解来保持HIF1α的升高水平，形成反馈环路，增强低氧时TET1的致癌性。因此，本研究揭示了TET1通过TET1和HIF1α之间的非酶交互作用在低氧环境下促进肿瘤形成和癌症进展的新的致癌机制，为癌症的新治疗靶点提供了启示。© 2023. 作者。

The classical oxidizing enzymatic activity of Ten Eleven Translocation 1 (TET1) and its tumor suppressor role are well known. Here, we find that high TET1 expression is associated with poor patient survival in solid cancers often having hypoxia, which is inconsistent with its tumor suppressor role. Through a series of in vitro and in vivo studies, using thyroid cancer as a model, we demonstrate that TET1 plays a tumor suppressor function in normoxia and, surprisingly, an oncogenic function in hypoxia. Mechanistically, TET1 mediates HIF1α-p300 interaction by acting as a co-activator of HIF1α to promote CK2B transcription under hypoxia, which is independent of its enzymatic activity; CK2 activates the AKT/GSK3β signaling pathway to promote oncogenesis. Activated AKT/GSK3β signaling in turn maintains HIF1α at elevated levels by preventing its K48-linked ubiquitination and degradation, creating a feedback loop to enhance the oncogenicity of TET1 in hypoxia. Thus, this study uncovers a novel oncogenic mechanism in which TET1 promotes oncogenesis and cancer progression through a non-enzymatic interaction between TET1 and HIF1α in hypoxia, providing novel therapeutic targeting implications for cancer.© 2023. The Author(s).