CREPT is required for the metastasis of triple-negative breast cancer (PRJCA040004)

CREPT (cell-cycle related and expression-elevated protein in tumors, also named RPRD1B) is a homologue of the yeast transcription termination factor Rtt103. Previous studies have shown that CREPT functions as an oncoprotein to promote tumorigenesis in different cancers, however, however, it has not been reported whether CREPT also plays an important role in the process of tumor metastasis. Here, we report that CREPT is a driver for the initiation of TNBC metastasis. We observed Upregulation of CREPT by recurrent somatic copy-number alterations at 20q11.23 correlates with initiation of TNBC metastasis. Depletion of CREPT profoundly reduced the metastatic ability of TNBC tumor cells in vitro and in vivo and led to downregulation of multiple metastatic genes related to extracellular matrix degradation, cell adhesion, secretion of inflammatory factors and angiogenesis. Mechanistically, we found that CREPT regulates the activity of enhancers in a p300-dependent manner and genome-wide analyses using Hi-C and HiChIP revealed that CREPT mediated 15472 enhancer-promoter loops and 2126 promoter-terminator loops, resulting in 1082 double loops which control the metastasis-associated gene expression. Disrupting the CREPT-mediated double loops using CRISPR-dCas9 targeting super-enahcner significantly reduced the gene expression and TNBC metastasis in vivo. More importantly, Using an AAV system to deplete CREPT expression significantly inhibited TNBC metastasis in both preventative and therapeutic mouse models. We propose that targeting CREPT to eliminate the double-loop formation could be a therapeutic strategy for the therapy of aggressive metastatic triple-negative breast cancers.