p53-induced RNA-binding protein ZMAT3 inhibits transcription of a hexokinase to suppress mitochondrial respiration in human cancer cells.

Abstract

The tumor suppressor p53 is a transcription factor that controls the expression of hundreds of genes. Emerging evidence indicates that the p53-induced RNA-binding protein ZMAT3 acts as a key splicing regulator that contributes to p53-dependent tumor suppression in vitro and in vivo. However, the mechanism by which ZMAT3 functions within the p53 pathway remains largely unclear. Here, we discovered a function of ZMAT3 in inhibiting transcription of <i>HKDC1</i>, a hexokinase that regulates glucose metabolism and mitochondrial respiration in human cancer cells. Quantitative proteomics revealed HKDC1 as the most significantly upregulated protein in <i>ZMAT3</i>-depleted colorectal cancer cells. <i>ZMAT3</i> depletion resulted in increased mitochondrial respiration, which was rescued by simultaneous depletion of <i>HKDC1</i>, suggesting that HKDC1 is a critical downstream effector of <i>ZMAT3</i>. Unexpectedly, ZMAT3 did not bind to <i>HKDC1</i> RNA or DNA; however, proteomic analysis of the ZMAT3 interactome identified its interaction with the oncogenic transcription factor JUN. ZMAT3 depletion enhanced JUN binding to the <i>HKDC1</i> locus, leading to increased <i>HKDC1</i> transcription that was rescued upon <i>JUN</i> depletion, suggesting that JUN activates <i>HKDC1</i> transcription in ZMAT3-depleted cells. Collectively, these findings uncover a mechanism by which ZMAT3 regulates transcription through JUN and demonstrate that <i>HKDC1</i> is a key component of the ZMAT3-regulated transcriptome in the context of mitochondrial respiration regulation.