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Defects in the FAcilitates Chromatin Transcription (FACT) complex, a histone chaperone composed of SSRP1 and SUPT16H, are implicated in intellectual disability. Here, we reveal that the FACT complex promotes glycolysis and sustains the correct cell fate of neural stem cells/neuroblasts in the Drosophila 3rd instar larval central brain. We show that the FACT complex binds to the promoter region of the estrogen-related receptor (ERR) gene and positively regulates ERR expression. ERR is known to act as an aerobic glycolytic switch by upregulating the enzymes required for glycolysis. Dysfunction of the FACT complex leads to the downregulation of ERR transcription, resulting in a decreased ratio of glycolysis to oxidative phosphorylation (G/O) in neuroblasts. Consequently, neuroblasts exhibit smaller cell sizes, lower proliferation potential, and altered cell fates. Overexpression of ERR or suppression of mitochondrial oxidative phosphorylation in neuroblasts increases the relative G/O ratio and rescues defective phenotypes caused by dysfunction of the FACT complex. Thus, the G/O ratio, mediated by the FACT complex, plays a crucial role in neuroblast cell fate maintenance. Our study may shed light on the mechanism by which mutations in the FACT complex lead to intellectual disability in humans., (© The Author(s) (2024). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)

Summary: Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.

A cure for human immunodeficiency virus type‐1 (HIV‐1) has been hampered by the limitation of current combination antiretroviral therapy (cART) to address the latent reservoirs in HIV‐1 patients. One strategy proposed to eradicate these reservoirs is the "shock and kill" approach, where latency‐reversing agents (LRAs) are used to reactivate and promote viral cell death and/or immune killing of reactivated cells. Here, we report that curaxin CBL0137, an antitumor compound, can potentiate tumor necrosis factor‐α‐mediated reactivation of latently infected HIV‐1cell lines. Additionally, the single use of CBL0137 is sufficient to reactivate HIV‐1 latent reservoirs in peripheral mononuclear cells (PBMCs) isolated from HIV‐1 positive, cART‐treated, aviremic patients. Thus, CBL0137 possesses capabilities as a LRA and could be considered for the "shock and kill" approach. Highlight: The present work identifies the anti‐tumor compound, curaxin CBL0137, as a latency reversing agent (LRA) capable of reactivating HIV‐1 latent reservoirs. Specifically, CBL0137 was able to reactivate latently infected HIV‐1 cell lines in combination with TNFα. Moreover, viral reservoirs isolated from HIV‐1, cART‐treated, aviremic patients were susceptible to induction by CBL0137 alone and in combination with TNFα for one donor. These observations support the use of CBL0137 as a future therapeutic option to address HIV‐1 latency. [ABSTRACT FROM AUTHOR]

Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG. [Display omitted] • CBL0137 inhibits DIPG tumor growth and restores H3K27me3 through FACT inhibition • Co-administration of CBL0137 and panobinostat enhances survival in DIPG xenografts • CBL0137 and panobinostat synergistically inhibit the Rb/E2F1 pathway and restore H3K27me3 Ehteda et al. find that the histone chaperon FACT is an oncogenic target in diffuse intrinsic pontine glioma. Pharmacological inhibition of FACT with CBL0137 reverses the effect of H3K27M. Co-administration of CBL0137 and panobinostat significantly prolongs survival in two aggressive DIPG in vivo models. [ABSTRACT FROM AUTHOR]