Oncogenesis

Oncogenesis

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

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-six-phosphate dehydrogenase, the rate-limiting enzyme in the pentose phosphate pathway. By activating the pentose phosphate pathway, 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 pentose phosphate pathway-mediated tumorigenesis in a p fifty-three-independent manner. Taken together, these findings reveal a novel role for p52-ZER6 in regulating glucose-six-phosphate dehydrogenase transcription via a p fifty-three-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.

INTRODUCTION

Tumor metabolic reprogramming is a hallmark of malignancy and plays a crucial role in meeting the cell's biogenesis demands and rapid proliferation. Furthermore, it facilitates tumor cell survival in response to certain genetic and environmental stressors. Glucose metabolic reprogramming, known also as the Warburg effect, occurs when tumor cells increase their glycolytic rate and exhibit a preference for glycolysis followed by lactate fermentation, instead of oxidative phosphorylation, even in the presence of sufficient oxygen. This phenomenon favors various branch reactions that yield glycolytic intermediates for downstream anabolic processes. One such branch is the pentose phosphate pathway involved in glucose catabolism. The pentose phosphate pathway is critical for tumor cell proliferation, as well as for maintaining the redox balance under stress conditions. Furthermore, it produces ribose-five-phosphate, a building block for ribonucleotides essential in DNA synthesis, and provides nicotinamide adenine dinucleotide phosphate, a cellular reductant important for lipid biosynthesis and for maintaining cellular redox homeostasis by scavenging reactive oxygen species. Due to its critical role in tumorigenesis, targeting glucose-six-phosphate dehydrogenase, the first rate-limiting enzyme in the pentose phosphate pathway, has attracted attention as a potential strategy for treating tumors, even though the regulatory mechanism controlling the pentose phosphate pathway is not fully understood.

Zinc-finger estrogen receptor interaction clone six is a transcription factor that contains six Cys two His two zinc-finger domains. ZER6 can be spliced into two isoforms with similar carboxyl termini but different amino termini, namely p fifty-two-ZER6 and p seventy-one-ZER6. p seventy-one-ZER6 has a HUB-one domain and a full-length KRAB domain; whereas p fifty-two-ZER6 does not contain the HUB-one domain and possesses only a truncated KRAB domain. Even though it was discovered twenty years ago, its biological and pathological functions remain unknown, and only recently, p fifty-two-ZER6 was identified as an oncogene that could enhance tumorigenesis by promoting ubiquitination/proteasomal degradation of tumor suppressor p fifty-three. Furthermore, while various C2H2 zinc finger proteins could regulate tumor metabolic reprogramming, whether ZER6 is involved in this process remains elusive.

In this study, we aimed to determine the role of p fifty-two-ZER6 in the metabolic reprogramming of tumor cells. We identified glucose-six-phosphate dehydrogenase as a novel target of p fifty-two-ZER6. Through in vitro and in vivo experiments, we found that p fifty-two-ZER6 could activate glucose-six-phosphate dehydrogenase transcription, leading to an increase in pentose phosphate pathway activity and, in turn, tumorigenesis. Furthermore, we show that p fifty-two-ZER6-mediated regulation of glucose-six-phosphate dehydrogenase occurs in a p fifty-three-independent manner, most plausibly through direct binding of p fifty-two-ZER6 to the glucose-six-phosphate dehydrogenase promoter. Hence, this study reveals p fifty-two-ZER6 as a novel regulator of the pentose phosphate pathway and, thereby, tumor progression. Importantly, this study points to p fifty-two-ZER6 as a new target for anti-tumor therapeutic strategies.