Abstract
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.
Statement of Significance De novo lipogenesis is a hallmark of many cancers, including glioblastoma; therefore, revealing how fatty acid synthesis enzymes are regulated may open up new venues in therapy. Moreover, understanding how epigenetic control of key cancer genes occurs may contribute to shed light on common regulatory mechanisms shared by other tumor suppressors in different cancers.
Footnotes
The authors declare no potential conflicts of interest.