Medulloblastomas (MBs) are aggressive brain cancers and represent the most common primary malignant tumour in children. Current treatment protocols involve an intensive regimen of surgery, radiation therapy and chemotherapy, guided by histopathology and risk stratification. Unfortunately, disease relapse proves fatal in 30% of cases, and treatment efficacy is compromised as MB cells develop resistance. Therefore, there is a critical need for more effective and tolerable therapies, especially for the treatment of aggressive MBs associated with a poor prognosis. Lipid metabolism reprogramming, characterized by increased cholesterol synthesis, lipid uptake and the activation of de novo lipogenesis, is a newly identified hallmark of cancers. Cholesterol is an essential structural component of membranes that contributes to membrane integrity and fluidity. Recently, increasing evidence has indicated that cholesterol is a major determinant by modulating cell signalling events governing the hallmarks of cancer. Our research demonstrates there is an overexpression of cholesterol metabolism in group 3 (G3), and group 4 (G4) MB subgroups compared to Sonic Hedgehog (SHH)-MB subgroup. In these tumours, cholesterol metabolism supports cell migration through the Rho-GTPase signalling pathway. Notably, we observed that shifting the culture conditions from 2D to 3D significantly upregulates lipid metabolism. Furthermore, spheroids derived from G3/G4-MBs and SHH-MBs show similar sensitivity to low doses of simvastatin. We validated these findings in a xenograft mouse model, where treatment with low doses of simvastatin led to increased survival time and remarkably, also reduced the metastatic spread of MB cells to the spinal cord. These results suggest that simvastatin holds potential as an adjuvant treatment for patients with medulloblastoma.
© 2025. The Author(s).

Inhibitors of protein synthesis hold promise for cancer therapy because many cancer driver proteins are unstable and blocking synthesis leads to their depletion. We described previously SVC112, a small molecule inhibitor of translation elongation that inactivates Head and Neck Squamous Cell Carcinoma (HNSCC) stem cells in vitro and prevents the regrowth of HNSCC tumor xenografts in mice after radiation treatment. Here we report that SVC112 also shows activity on its own (without radiation) but with a 1600-fold range in growth inhibition among cancer cell lines of various origins. Our efforts to define molecular correlates of SVC112 sensitivity found that basal expression of apoptosis/survival factors correlates with SVC112-induced apoptosis in hematologic cancer cell lines, while phosphorylation of c-Myc correlates with sensitivity to SVC112 in colorectal cancer cell lines. Apoptosis induction by SVC112 predicts tumor growth control and survival benefit in mouse xenograft models. We suggest a paradigm wherein utility of translation inhibitors is defined by (1) inherent dependence of cancer cells on specific survival factors and (2) post-translational modifications that affect the stability of oncogenic driver proteins.
© 2025. The Author(s).

Circulating blood platelets are responsible for maintaining hemostasis. They are released into blood vessels from mature megakaryocytes. Although several transcription factors have been reported to orchestrate the transcriptional programs required for platelet production, how chromatin regulators control these processes is still poorly understood. MLL3 and MLL4 are the main lysine methyltransferases responsible for the deposition of H3K4me1 histone marks at enhancers. MLL3 and MLL4 typically form complexes with other co-factors, such as PTIP. Recently, we showed that loss of PTIP leads to decreased platelet numbers in mice. Here, we find that, although MLL3/4 double deficiency does not alter megakaryopoiesis and endomitosis, the final step of megakaryocyte maturation is affected due to an abnormal cytoskeleton and demarcation membrane system. MLL3/4 double-deficient mice develop macrothrombocytopenia; platelets are preactive and pro-apoptotic, leading to their rapid clearance from the circulation. Increased megakaryopoeisis in the bone marrow and spleen cannot compensate for these abnormalities. Mechanistically, the expression of genes responsible for normal megakaryocyte function and platelet production is altered in MLL3/4-deficient megakaryocytes, partly due to impaired enhancer functions associated with these genes. Our findings provide insights into the epigenetic programs that are important for platelet biogenesis.
© 2025. The Author(s).

Epstein-Barr virus (EBV), a common gamma-herpesvirus linked to various malignancies, exploits host cellular mechanisms to promote oncogenesis. Our previous research identified the zinc finger protein ZC3H18 as a novel component of the cellular DNA replication machinery in the context of EBV-driven tumorigenesis. We now demonstrate that ZC3H18 expression is upregulated in EBV-transformed and cancer cell lines, as well as in EBV-positive diffuse large B-cell lymphomas from AIDS patients, compared to their EBV-negative counterparts, supporting its activation by EBV. Our experiments show that ZC3H18 expression is regulated by the key oncogenic factors STAT3 and MYC, as well as the essential viral protein EBNA1. Using inhibitors and genetic knockdown, we find that suppressing STAT3, MYC, or EBNA1 leads to decreased ZC3H18 levels, reduced cell viability, and increased apoptosis in EBV-positive B lymphoma cells. Furthermore, ZC3H18, STAT3, MYC, and EBNA1 mutually support each other's expression through a complex transcriptional network. Notably also, ZC3H18 transcriptionally enhances components of the NF-κB pathway, contributing to NF-κB signaling even in the absence of the EBV oncoprotein LMP1, which is crucial for cell proliferation and survival of several EBV-associated malignancies. Our findings reveal a novel regulatory axis in EBV-positive cancer cells involving STAT3, MYC, EBNA1, & ZC3H18, also linking ZC3H18 to the NF-κB pathway independently of LMP1. The involvement of EBNA1 in this network may explain, at least in part, the preferential upregulation of ZC3H18 in EBV-associated tumors and highlights predictive and therapeutic possibilities for such cancers.
Copyright: © 2025 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Acute megakaryoblastic leukemia (AMKL) is a rare hematological malignancy in adults but children. Alternative splicing (AS) has been shown to affect hematological cancer progression, making splicing factors promising targets. Our research aims to investigate the efficacy of the molecular glue degrader indisulam, which targets the splicing factor RNA binding motif protein 39 (RBM39) in AMKL models.
Public drug sensitivity data analysis revealed that AMKL cell lines exhibited the highest sensitivity to indisulam compared with other tumor types. Then we confirmed that RBM39 depletion by indisulam treatment induced AMKL cell cycle arrest and apoptosis. In AMKL mouse model, indisulam treatment significantly reduced the leukemic burden and prolonged the lifetime of AMKL mice. Mechanically, integration of transcriptomic and proteomic analyses revealed that indisulam-mediated RBM39 degradation resulted in AS of the transcription factor zinc finger MYND-type containing 8 (ZMYND8), an AMKL cell growth regulator. Finally, the effectiveness of indisulam depended on DDB1- and Cul4- Associated Factor 15 (DCAF15) expression because knockout of DCAF15 rescued the indisulam-induced RBM39 degradation and mis-splicing of ZMYND8.
Indisulam is a promising therapeutic candidate for AMKL and the RBM39-mediated ZMYND8 splicing plays an important role in promoting the development of AMKL.
© 2025. The Author(s).