Cancer cells rewire metabolic pathways to enable their uncontrolled proliferation through a phenomenon called the Warburg effect. Cancer cells adopt this metabolic diversion through epigenetic modifications such as chromatin remodeling and histone acetylation (H3k27ac). Such inheritable modifications influence DNA accessibility to regulate gene expression. One such epigenetic modifier, WD40 protein, is shown to be involved in regulation of transcription, and protein modifications. Its dysfunction might influence the development of diseases such as cancer and metabolic diseases. Our lab has discovered a WD40 containing protein which we refer to as WD40 that serves as an oncogenic driver in breast cancer cells. Based on preliminary findings, we propose that WD40 functions as an oncogenic driver, which plays a critical role in epigenetic reprogramming in genes that drive the Warburg effect and that promote the enrichment of CD44high/CD24low population.
/Results: We determined endogenous levels of WD40 in different breast cancer cells and found that WD40 is markedly elevated in breast cancer cell lines.
Methods/Results (Cont): WD40 knockdown growth curve assays revealed that breast cancer cells depend on WD40 for their growth. Further, recombinant WD40 expression in normal mammary epithelial cells initiates a transcriptional program that is coupled to the emergence of both tumor spheres and strong tumor-promoting properties in vivo (NOD-SCID). Transcriptomic and metabolomic analysis revealed that WD40 orchestrates dramatic reprogramming of the glycolytic infrastructure of breast cancer stem cells and promotes enrichment of CD44high/CD24low population. Furthermore, our ChIP assay results indicate that WD40 increases H3k27ac signature on promoter/HRE regions of its key target genes to facilitate their transcription.
Taken together, breast cancer cells have elevated WD40 and depend on WD40 for survival. Recombinant WD40 expression results in tumor formation in NOD-SCID mice. WD40 initiates aerobic glycolysis and promotes enrichment of CD44high/CD24low phenotype. This knowledge can be used to design novel therapeutic strategies to reverse epigenetic modifications in cancer.
University of Toronto
Connaught Fund
The author has declared no conflicts of interest.