SETD5 regulates glycolysis in breast cancer stem-like cells and fuels tumor growth

Am J Pathol. 2022 Jan 18:S0002-9440(22)00006-2. doi: 10.1016/j.ajpath.2021.12.006. Online ahead of print.ABSTRACTAlthough Glycolysis plays a pivotal role in breast cancer stem-like cells (BCSCs) reprogramming, the molecular mechanisms that couple glycolysis to cancer stem-like cell remain unclear. The SET-domain containing 5 (SETD5) is a previously uncharacterized member of the histone lysine methyltransferase family. The goal of this study was to explore the mechanisms underlying the promotion of stem-like and glycolysis activation traits by SETD5. Previous study displayed that overexpression of SETD5 in breast cancer (BC) tissues is positively associated with progression. The present study showed that SETD5 expression was enriched in BCSC. Downregulation of SETD5 significantly decreased BCSC properties and glycolysis in vitro and in vivo. Interestingly, SETD5 and glycolytic enzymes were accumulated in the central hypoxic regions of subcutaneous tumor tissues. Bioinformatic analysis predicted SETD5 binding to EP300, and then hypoxia-inducible factor 1α (HIF-1α). Our mechanistic study found that SETD5 is an upstream effector of EP300/HIF-1α. SETD5 knockdown reduced the expression of HIF-1α, hexokinase-2, and 6-phosphofructo-2-kinase in the nucleus after treatment with cobalt chloride (CoCl2), a chemical hypoxia mimetic agent, which activates HIF-1α to accumulate in the nucleus. Therefore, SETD5 is required for glycolysis in BCSCs through binding to EP300/HIF-1α and coul...
Source: The American Journal of Pathology - Category: Pathology Authors: Source Type: research