The p52-ZER6/G6PD axis alters aerobic glycolysis and promotes tumor progression by activating the pentose phosphate pathway

Abstract

Abnormal glucose metabolism is a highlight of tumor metabolic reprogramming and is closely related to the development of malignancies. p52-ZER6, a C2H2-type zinc finger protein, promotes cell proliferation and tumorigenesis. However, its role in the regulation of biological and pathological functions remains poorly understood. Here, we examined the role of p52-ZER6 in tumor cell metabolic reprogramming. Specifically, we demonstrated that p52-ZER6 promotes tumor glucose metabolic reprogramming by positively regulating the transcription of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway (PPP). By activating the PPP, p52-ZER6 was found to enhance the production of nucleotides and nicotinamide adenine dinucleotide phosphate, thereby providing tumor cells with the building blocks of ribonucleic acids and cellular reductants for reactive oxygen species scavenging, which subsequently promotes tumor cell proliferation and viability. Importantly, p52-ZER6 promoted PPP-mediated tumorigenesis in a p53-independent manner. Taken together, these findings reveal a novel role for p52-ZER6 in regulating G6PD transcription via a p53-independent process, ultimately resulting in tumor cell metabolic reprogramming and tumorigenesis. Our results suggest that p52-ZER6 is a potential target for the diagnosis and treatment of tumors and metabolic disorders.

The Emerging Roles of the Metabolic Regulator G6PD in Human Cancers

“…Moreover, enhanced dimerization of G6PD, either through a knockdown of factors that inhibit G6PD dimerization, such as p53 and Bcl-2-associated athanogene 3 (BAG3) [67,118], or through overexpression of factors that promote G6PD dimerization, such as PLK1 [83], can also enhance G6PD/PPP. Meanwhile, inhibition of G6PD/PPP through G6PD knockdown results in decreased tumor cell proliferation [20,21,75,78]. These studies underscore that G6PD, through its role in counteracting ROS imbalance, helps cells avoid cell cycle arrest and enhances proliferation.…”

“…G6PD upregulation in tumor cells enhances their anti-oxidant activity, helping in the maintenance of ROS balance, preventing cell cycle arrest, and enhancing proliferation [10,124]. Our previous findings demonstrated that positive regulation of G6PD transcriptional activity by various transcription factors (including YY1, NeuroD1, PBX3, and p52-ZER6) enhances tumor cell proliferation by promoting tumor cell nucleotides and lipid biosynthesis [20,21,75,78].…”

“…YY1 binds to the G6PD promoter and acts as a transcriptional activator, thereby enhancing the PPP and subsequently promoting tumorigenesis. Our previous studies also showed that Pre-B-cell leukemia transcription factor 3 (PBX3) and the p52-ZER6 isoform of zinc-finger 398 (ZNF398, also known as ZER6) could promote tumorigenic potential by upregulating G6PD transcriptional activity and the PPP [21,75]. Furthermore, Zhang et al revealed that knocking down nuclear factor erythroid 2-related factor 2 (Nrf2) suppresses the activation of PPP enzymes, including G6PD, in breast cancer [89].…”

ZNF471 Interacts with BANP to Reduce Tumour Malignancy by Inactivating PI3K/AKT/mTOR Signalling but is Frequently Silenced by Aberrant Promoter Methylation in Renal Cell Carcinoma

“…Under normal physiological conditions, regulatory factors involved in tumour occurrence and development are inactive, and some KRAB-ZNFs participate in negative regulation of these factors. In the process of tumour occurrence and further development influenced by external factors, some KRAB-ZNFs could also play a negative role in tumour occurrence and development 16 - 17 . It has been found that members of the KRAB-ZNF family play an important role in RCC, a finding helpful for obtaining a better understanding of the molecular mechanism of RCC occurrence and searching for potential molecular markers for the diagnosis and treatment of RCC 18 .…”