Identification and experimental validation of druggable epigenetic targets in hepatoblastoma

• DOI: 10.1016/j.jhep.2023.05.031
• Publication Date: 2023-06-10T14:03:13Z
• Authors: Alex Clavería-Cab...; Jose Maria Herranz; Maria Ujue Latasa; Maria Arechederra; Iker Uriarte; Antonio Pineda-Lu...; Felipe Prosper; Pedro Berraondo; Cristina Alonso; Bruno Sangro; Jose Juan García ...; Maria Luz Martine...; Sergio Ciordia; Fernando José Cor...; Paola Francalanci; Rita Alaggio; Jessica Zucman-Rossi; Emilie Indersie; Stefano Cairo; Montserrat Doming...; Laura Zanatto; Pau Sancho-Bru; Carolina Armengol; Carmen Berasain; Maite García Fern...; Matias Antonio Avila
• Keywords: Hepatoblastoma; Epigenetic Therapy

Hepatoblastoma (HB) is the most frequent childhood liver cancer. Patients with aggressive tumors have limited therapeutic options; therefore, a better understanding of HB pathogenesis needed to improve treatment. HBs very low mutational burden; however, epigenetic alterations are increasingly recognized. We aimed identify regulators consistently dysregulated in and evaluate efficacy their targeting clinically relevant models.We performed comprehensive transcriptomic analysis 180 genes. Data from fetal, pediatric, adult, peritumoral (n = 72) tumoral 91) tissues were integrated. Selected drugs tested cells. The target identified was validated primary cells, organoids, patient-derived xenograft model, genetic mouse model. Transcriptomic, proteomic metabolomic mechanistic analyses performed.Altered expression genes regulating DNA methylation histone modifications observed association molecular clinical features poor prognosis. methyltransferase G9a markedly upregulated traits increased malignancy. Pharmacological significantly inhibited growth organoids xenografts. Development induced by oncogenic forms β-catenin YAP1 ablated mice hepatocyte-specific deletion G9a. that undergo significant transcriptional rewiring involved amino acid metabolism ribosomal biogenesis. inhibition counteracted these pro-tumorigenic adaptations. Mechanistically, potently repressed c-MYC ATF4, master metabolic reprogramming.HBs display profound dysregulation machinery. key effectors exposes vulnerabilities can be leveraged treatment patients.In spite recent advances management hepatoblastoma (HB), resistance drug toxicity still major concerns. This systematic study reveals remarkable tissues. Through pharmacological experimental approaches, we demonstrate histone-lysine-methyltransferase an excellent HB, which also harnessed enhance chemotherapy. Furthermore, our highlights cells orchestrated coordination oncogene. From broader perspective, findings suggest anti-G9a therapies may effective other c-MYC-dependent tumors.