Hypoxia switches TET1 from being tumor-suppressive to oncogenic

Yang，Qi1,2,3; Dang，Hui2; Liu，Jiaxin1; Wang，Xingye1,4; Wang，Jingyuan1,5; Lan，Xinhui2; Ji，Meiju1,6; Xing，Mingzhao7; Hou，Peng1,2

2023

10.1038/s41388-023-02659-w

Oncogene   Impact Factor & Quartile

0950-9232

1476-5594

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.

SCI

English

Corresponding

Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity

Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity

WOS:000964663400001

SPRINGERNATURE

MOLECULAR BIOLOGY & GENETICS

2-s2.0-85151522904

Scopus

1.Key Laboratory for Tumor Precision Medicine of Shaanxi Province,The First Affiliated Hospital of Xi’an Jiaotong University,Xi’an,710061,China
2.Department of Endocrinology,The First Affiliated Hospital of Xi’an Jiaotong University,Xi’an,710061,China
3.Department of Otorhinolaryngology-Head and Neck Surgery,The First Affiliated Hospital of Xi’an Jiaotong University,Xi’an,710061,China
4.Department of Structural Heart Disease,The First Affiliated Hospital of Xi’an Jiaotong University,Xi’an,710061,China
5.Department of Clinical Laboratory,The First Affiliated Hospital of Xi’an Jiaotong University,Xi’an,710061,China
6.Center for Translational Medicine,The First Affiliated Hospital of Xi’an Jiaotong University,Xi’an,710061,China
7.School of Medicine,Southern University of Science and Technology,Shenzhen,Guangdong,518055,China

Yang，Qi,Dang，Hui,Liu，Jiaxin,et al. Hypoxia switches TET1 from being tumor-suppressive to oncogenic[J]. Oncogene,2023.

Yang，Qi.,Dang，Hui.,Liu，Jiaxin.,Wang，Xingye.,Wang，Jingyuan.,...&Hou，Peng.(2023).Hypoxia switches TET1 from being tumor-suppressive to oncogenic.Oncogene.

Yang，Qi,et al."Hypoxia switches TET1 from being tumor-suppressive to oncogenic".Oncogene (2023).