ZMIZ1 promotes aerobic glycolysis and development of hepatocellular carcinoma through inducing NOTCH1-mediated transcription of PYCR1

Abstract

Hepatocellular carcinoma (HCC) is characterized by profound metabolic reprogramming that promotes tumor progression. Although zinc finger MIZ-type containing 1 (ZMIZ1) has been implicated in several malignancies, its biological function and underlying mechanism in HCC remain unclear. The expression and clinical significance of ZMIZ1 and PYCR1 were evaluated using public datasets, clinical specimens, and tissue microarrays. Gain- and loss-of-function studies, rescue experiments, xenograft models, and molecular assays were performed to investigate their biological functions and regulatory mechanisms. ZMIZ1 was significantly upregulated in HCC tissues and associated with unfavorable patient outcomes. Functional studies demonstrated that ZMIZ1 promoted HCC cell proliferation, migration, tumor growth, and glycolytic metabolic reprogramming. Mechanistically, PYCR1 was identified as a critical downstream effector of ZMIZ1, and reciprocal rescue experiments confirmed that PYCR1 mediated the oncogenic effects of ZMIZ1 both in vitro and in vivo. Further analyses revealed that ZMIZ1 physically interacted with NOTCH1, enhanced its nuclear accumulation, and promoted NOTCH1-dependent transcriptional activation of PYCR1. Promoter mutation assays identified a functional NOTCH1-responsive element required for this regulation. Moreover, only wild-type PYCR1, but not a catalytically inactive mutant, restored the impaired glycolytic and proliferative phenotypes caused by ZMIZ1 depletion, indicating that PYCR1 functions in an enzyme activity-dependent manner. Finally, the ZMIZ1/NOTCH1/PYCR1 axis promoted glycolytic reprogramming through activation of PI3K/AKT signaling. ZMIZ1 promotes HCC progression by enhancing NOTCH1-mediated transcriptional activation of PYCR1, thereby driving PI3K/AKT-dependent glycolytic metabolic reprogramming. These findings identify the ZMIZ1/NOTCH1/PYCR1 signaling axis as a critical regulator of HCC progression and a potential therapeutic target for HCC.