Phosphocreatine Promotes Epigenetic Reprogramming to Facilitate Glioblastoma Growth through Stabilizing BRD2

The research results, completed in collaboration by many scientists including Lishu Chen, Qinghui Qi, and Xiaoqing Jiang, were published in the groundbreaking journal Cancer Discovery. The report detailed how phosphocreatine (PCr) promotes the growth of glioblastoma (GBM) by stabilizing bromodomain-containing protein 2 (BRD2). This discovery provides a new perspective for the treatment of glioblastoma.

Glioblastoma is the most common and deadliest malignant brain tumor, with very low survival rates. While metabolic reprogramming of tumors is considered one of the hallmarks of cancer, the specific metabolic characteristics of glioblastoma are not yet fully understood. Researchers have found a special cell subpopulation in GBM with self-renewal capabilities, known as GBM stem cells (GSCs), which play a key role in tumor development and resistance to GBM treatment. Recent studies have shown that GSCs produce a large amount of PCr and thereby remodel their chromatin landscape to evade the inhibitory effects of interferons.

PCr is an important natural metabolite that plays a key role in energy metabolism, primarily found in cells with high energy metabolism such as neurons and muscle cells. Creatine kinase is a crucial enzyme responsible for the phosphorylation transfer from ATP to creatine (Cr), generating PCr. Compared to ATP, the PCr molecule is smaller and carries fewer negative charges, making it highly suitable for maintaining and replenishing local ATP levels, thus acting as an energy buffer. Beyond this well-known role in energy regulation, an increasing body of evidence suggests other functions of PCr. For example, PCr can interact with phospholipids to protect cell membranes from damage, and in the nervous system, PCr has neuroprotective effects against hypoxia, ischemia, oxidative stress, and apoptosis. Additionally, studies have shown that various types of cancer use PCr for energy buffering to support their survival and promote metastasis.

In this study, the team revealed that GBM stem cells promote the production of PCr by remodeling the epigenetic landscape, mediated through the upregulation of brain-type creatine kinase transcription by zinc finger e-box binding homeobox 1 (ZEB1). PCr competes with E3 ubiquitin ligase SPOP for BRD2 binding, inhibiting the polyubiquitination of BRD2, thereby promoting chromosomal segregation and cell proliferation in GBM stem cells. Importantly, pharmaceutical interference with cyclocreatine led to BRD2 degradation in cells, inhibiting the transcription of its target proteins, thereby suppressing chromosomal segregation and cell proliferation. Notably, cyclocreatine treatment significantly hindered tumor growth in a mouse GBM model and made the tumors more sensitive to BRD2 inhibitors without detectable side effects. These findings highlight that high production of PCr is a targetable metabolic characteristic of GBM and could serve as a promising target for GBM treatment in the future.

This critical research, which has potential contributions to GBM treatment, unveiled the role of PCr as an important metabolite in the progression of GBM, providing a new metabolic target and proposing new research directions for the treatment of glioblastoma. With further research and clinical trials, these findings could be translated into concrete therapeutic strategies to provide new treatment options for GBM patients.