| First Author | Yang Q | Year | 2023 |
| Journal | Oncogene | Volume | 42 |
| Issue | 20 | Pages | 1634-1648 |
| PubMed ID | 37020036 | Mgi Jnum | J:336129 |
| Mgi Id | MGI:7486600 | Doi | 10.1038/s41388-023-02659-w |
| Citation | Yang Q, et al. (2023) Hypoxia switches TET1 from being tumor-suppressive to oncogenic. Oncogene 42(20):1634-1648 |
| abstractText | 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 HIF1alpha-p300 interaction by acting as a co-activator of HIF1alpha to promote CK2B transcription under hypoxia, which is independent of its enzymatic activity; CK2 activates the AKT/GSK3beta signaling pathway to promote oncogenesis. Activated AKT/GSK3beta signaling in turn maintains HIF1alpha 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 HIF1alpha in hypoxia, providing novel therapeutic targeting implications for cancer. |
