p53-induced RNA-binding protein ZMAT3 inhibits transcription of a hexokinase to suppress mitochondrial respiration

Area of Science:

• Molecular Biology
• Cancer Research
• Cellular Metabolism

Background:

• The tumor suppressor p53 is a transcription factor regulating numerous genes.
• ZMAT3, induced by p53, is an RNA-binding protein crucial for p53-dependent tumor suppression.
• The precise mechanism of ZMAT3's function in the p53 pathway remains largely unknown.

Purpose of the Study:

• To elucidate the mechanism by which ZMAT3 functions in the p53 pathway.
• To identify downstream targets and regulatory interactions of ZMAT3.
• To understand ZMAT3's role in regulating cellular metabolism and tumor suppression.

Main Methods:

• Quantitative proteomics to identify proteins upregulated upon ZMAT3 depletion.
• Gene expression analysis to assess HKDC1 transcription.
• CRISPR-mediated gene depletion to validate effector molecules (HKDC1, JUN).
• Chromatin immunoprecipitation to assess JUN binding to the HKDC1 promoter.

Main Results:

• ZMAT3 depletion significantly upregulates HKDC1, a key regulator of glucose metabolism and mitochondrial respiration.
• ZMAT3 depletion leads to increased mitochondrial respiration, which is reversed by HKDC1 depletion.
• ZMAT3 interacts with the oncogenic transcription factor JUN, not directly with HKDC1 DNA or RNA.
• ZMAT3 depletion increases JUN binding to the HKDC1 promoter, driving HKDC1 transcription; JUN depletion rescues this effect.

Conclusions:

• ZMAT3 inhibits HKDC1 transcription, likely by preventing JUN binding to the HKDC1 promoter.
• HKDC1 is a critical downstream effector of ZMAT3 in regulating mitochondrial respiration.
• This study reveals a novel mechanism of ZMAT3-mediated transcriptional regulation and its role in controlling cellular metabolism within the p53 tumor suppressor pathway.