A chemical biology approach reveals a dependency of glioblastoma on biotin distribution.

Glioblastoma (GBM) is a uniformly lethal disease driven by glioma stem cells (GSCs). Here, we use a chemical biology approach to unveil previously unknown GBM dependencies. By studying sulconazole (SN) with anti-GSC properties, we find that SN disrupts biotin distribution to the carboxylases and histones. Transcriptomic and metabolomic analyses of SN-treated GSCs reveal metabolic alterations that are characteristic of biotin-deficient cells, including intracellular cholesterol depletion, impairment of oxidative phosphorylation, and energetic crisis. Furthermore, SN treatment reduces histone biotinylation, histone acetylation, and expression of superenhancer-associated GSC critical genes, which are also observed when biotin distribution is genetically disrupted by holocarboxylase synthetase (HLCS) depletion. HLCS silencing impaired GSC tumorigenicity in an orthotopic xenograft brain tumor model. In GBM, high HLCS expression robustly indicates a poor prognosis. Thus, the dependency of GBM on biotin distribution suggests that the rational cotargeting of biotin-dependent metabolism and epigenetic pathways may be explored for GSC eradication.

Epigenetic plasticity and redox regulation of neural stem cell state and fate.

The neural stem cells (NSCs) are essential for normal brain development and homeostasis. The cell state (i.e. quiescent versus activated) and fate (i.e. the cell lineage of choice upon differentiation) of NSCs are tightly controlled by various redox and epigenetic regulatory mechanisms. There is an increasing appreciation that redox and epigenetic regulations are intimately linked, but how this redox-epigenetics crosstalk affects NSC activity remains poorly understood. Another unresolved topic is whether the NSCs actually contribute to brain ageing and neurodegenerative diseases. In this review, we aim to 1) distill concepts that underlie redox and epigenetic regulation of NSC state and fate; 2) provide examples of the redox-epigenetics crosstalk in NSC biology; and 3) highlight potential redox- and epigenetic-based therapeutic opportunities to rescue NSC dysfunctions in ageing and neurodegenerative diseases.

Interweaving Tumor Heterogeneity into the Cancer Epigenetic/Metabolic Axis.

Significance: The epigenomic/metabolic landscape in cancer has been studied extensively in the past decade and forms the basis of various drug targets. Yet, cancer treatment remains a challenge, with clinical trials exhibiting limited efficacy and high relapse rates. Patients respond differently to therapy, which is fundamentally attributed to tumor heterogeneity, both across and within tumors. This review focuses on the interactions between the heterogeneous tumor microenvironment (TME) and the epigenomic/metabolic axis in cancer, as well as the emerging technologies under development to aid heterogeneity studies. Recent Advances: Interlinks between epigenetics and metabolism in cancer have been reported. Emerging studies have unveiled interactions between the TME and cancer cells that play a critical role in regulating epigenetics and reprogramming cancer metabolism, suggesting a three-way cross talk. Critical Issues: This cross talk accentuates the multiplex nature of cancer, and the importance of considering tumor heterogeneity in various epigenomic/metabolic cancer studies. Future Directions: With the advancement in single-cell profiling, it may be possible to identify cancer subclones and their unique vulnerabilities to develop a multimodal therapy. Drugs targeting the TME are currently being studied, and a better understanding of the TME in regulating cancer epigenetics and metabolism may hold the key to identifying novel therapeutic targets.