TRIM24 cooperates with CDKN2A deletion to drive astrocyte malignant transition by reprogramming mevalonate metabolism

Epigenetic dysregulation is a hallmark of glioma. However, the underlying mechanisms remain incompletely understood. Here, we identify the histone reader TRIM24 (Tripartite Motif Containing 24) as an oncogenic driver that promotes malignant transformation of mouse astrocytes by reprogramming mevalonate metabolism. In cooperation with CDKN2A deletion, but not TP53 loss, TRIM24 overexpression in mouse astrocytes induces a kind of aggressive glioma that recapitulates features of human gliosarcoma. Genomic analysis of The Cancer Genome Atlas (TCGA) data indicates that 57% (291/511) of patients harbor both TRIM24 amplification/gain and CDKN2A deletion in glioblastoma. Mechanistically, TRIM24 co-operated with the transcription factor Yin Yang 1 (YY1) to upregulate mevalonate pathway in a histone-dependent manner, thereby reprogramming cholesterol metabolism and driving malignant transition of astrocytes. This oncogenic interaction is competitively inhibited by p19Arf. Dual pharmacological inhibition of TRIM24 and the mevalonate pathway synergistically suppressed tumor growth. Thus, our findings define the TRIM24-YY1-mevalonate axis as a critical epigenetic-metabolic circuit driving malignant transition of astrocytes and highlight co-targeting this pathway with a TRIM24 bromodomain inhibitor and statins as a rational and translatable strategy.