CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulation

Abstract

Triple-negative breast cancer (TNBC) is recognized for its aggressiveness, yet the mechanism underlying metastasis remains unclear. Here, we report that CREPT/RPRD1B, which exhibits somatic gene copy-number amplifications and elevated expression, correlates with poor patient survival and drives TNBC metastasis. We demonstrate that CREPT alters three-dimensional genome structures in topologically-associating domain (TAD) status and chromatin loops via occupying promoters and enhancers. Specifically, CREPT mediates 1082 co-operational chromatin loops configured by enhancer-promoter and promoter-termination loops, which are validated by HiChIP analyses and visualized by Tn5-FISH experiments. These loops orchestrate RNAPII loading and recycling to enhance the metastatic gene expression. Disruption of these co-operational loops using CRISPR-dCas9 suppresses TNBC metastasis in vivo. Furthermore, depletion of CREPT using an AAV-based shRNA blocks TNBC metastasis in both preventative and therapeutic mouse models. We propose that targeting CREPT to disrupt the co-operational chromatin loop structures represents a promising therapeutic strategy for metastatic TNBC. • Somatic CREPT gene copy-number amplifications with elevated expression occur in the metastatic triple-negative breast cancer (TNBC) and correlate with poor patient survival • CREPT mediates 1082 co-operational chromatin loops configured by enhancer-promoter and promoter-termination loops • CREPT-mediated co-operational chromatin loops regulate metastatic genes during the metastasis of TNBC • Depleting CREPT by adeno-associated virus (AAV) blocks TNBC metastasis in preventative and therapeutic mouse models