An InDel Genomic Variant within a Bifunctional Super-Enhancer for LINC00636 and CD47 Regulation in Breast Cancer
Di Benedetto, C.; Tsark, A.; Acenas, D. D.; Thach, A.; Singal, A.; Opazo-Medallo, V.; Rodriguez, A.; El Zeini, M.; Zhang, H.; Park, C.; Gonzales-Velozo, H.; Weissman, I. L.; Betancur, P.
Show abstract
Highly accessible genomic super-enhancers often drive tumor-promoting programs, yet the impact of genomic variation within these regulatory elements remains unclear. Here, we identified a bifunctional super-enhancer that regulates the expression of cancer-promoting genes LINC00636 and CD47 in breast cancer. We discovered that a common germline insertion variant within the super-enhancer is associated with reduced chromatin accessibility at the super-enhancer locus. Deletion of the insertion in breast cancer cells increased chromatin accessibility, leading to upregulation of LINC00636 and CD47, enhanced resistance to nutrient-deprivation-induced apoptosis (mediated by CD47), activation of senescence (driven by elevated LINC00636), delayed cell death, and reduced infiltration of CD80 pro-inflammatory macrophages, changes that represent tumor-promoting features. Together, our findings uncover a common insertion-deletion variant that fine-tunes the regulatory activity of a bifunctional super-enhancer, suggest a protective role for the insertion allele, and establish a novel function for LINC00636 in senescence and breast cancer.
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