Myeloid translocation gene-16 co-repressor promotes degradation of hypoxia-inducible factor 1

Area of Science:

• Molecular Biology
• Cellular Metabolism
• Cancer Research

Background:

• Myeloid translocation gene 16 (MTG16) is a co-repressor that regulates gene expression.
• Hypoxia-inducible factor 1 (HIF1) is a transcription factor controlling glycolytic genes, crucial in cellular adaptation to low oxygen.
• The interplay between MTG16 and HIF1 in regulating glycolysis and mitochondrial respiration is not fully understood.

Purpose of the Study:

• To investigate the potential negative regulation of HIF1 by MTG16.
• To determine if MTG16 influences glycolysis and mitochondrial respiration through HIF1.
• To elucidate the molecular mechanisms underlying MTG16's role in HIF1 pathway.

Main Methods:

• Utilized a doxycycline Tet-On system to control MTG16 expression in Raji cells.
• Performed co-association studies, electrophoretic mobility shift assays (EMSAs), and chromatin immunoprecipitation (ChIP) assays.
• Investigated protein-protein interactions and DNA-binding activities related to MTG16 and HIF1.

Main Results:

• MTG16 was found to interact with HIF1α, requiring specific N-terminal residues (NHR1) of MTG16.
• MTG16 associated with hypoxia response elements (HREs) in glycolytic gene promoters (PFKFB3, PFKFB4, PDK1).
• MTG16 co-occupied glycolytic gene promoters with HIF1α and HIF1β, and promoted HIF1α ubiquitination and degradation via interaction with prolyl hydroxylase D2.

Conclusions:

• MTG16 negatively regulates HIF1α stability and activity, thereby inhibiting glycolysis.
• MTG16 is part of a protein complex that controls HIF1α levels, impacting cellular respiration.
• These findings expand the known functions of MTG co-repressors and highlight their role in metabolic regulation.