ZBTB18 interacts with CTBP2 and represses SREBP genes to inhibit fatty acid synthesis in glioblastoma

Enhanced fatty acid synthesis is a hallmark of tumors, including glioblastoma. SREBF1/2 regulates the expression of enzymes involved in fatty acid and cholesterol synthesis. Yet, little is known about the precise mechanism regulating SREBP gene expression in glioblastoma. Here, we show that a novel interaction between the co-activator/co-repressor CTBP2 and the tumor suppressor ZBTB18 regulates the expression of SREBP genes. Our study points at CTBP2 as a co-activator of SREBP genes whose complex activity is impaired by ZBTB18. ZBTB18 binding to the SREBP gene promoters is associated with reduced LSD1 activity leading to increased di-methylation of lysine 9 (H3K9me2), and concomitant decrease of H3K4me3 with consequent repression of the SREBP genes. In line with our findings, lipidomics analysis shows a reduction of several phospholipid species upon ZBTB18 expression. Our results thus outline a new epigenetic mechanism enrolled by ZBTB18 and its cofactors to regulate fatty acid synthesis which could be targeted to treat glioblastoma patients.