MMP‐9‐dependent proteolysis of the histone H3 N‐terminal tail: a critical epigenetic step in driving oncogenic transcription and colon tumorigenesis

Abstract

Matrix metalloproteinase 9 (MMP‐9) is a member of the MMP family and has been recently identified as a nuclear protease capable of clipping histone H3 N‐terminal tails (H3NT). This MMP‐9‐dependent H3NT proteolysis is critical for establishing an active state of gene transcription during osteoclast differentiation and melanoma development. However, whether H3NT cleavage by MMP‐9 plays a similar role in other cellular events has not been explored. Here, we dissect the functional contribution of MMP‐9‐dependent H3NT clipping to colonic tumorigenesis by using a combination of genome‐wide transcriptome data, ChIP/ChIPac‐qPCR, CRISPR/dCas9 gene‐targeting system, and in vivo xenograft models. We show that MMP‐9 is overexpressed in colon cancer cells and catalyzes H3NT proteolysis to drive transcriptional activation of growth stimulatory genes. Our studies using knockdown and inhibition approaches clearly indicate that MMP‐9 mediates transcriptional activation and promotes colonic tumorigenesis in a manner dependent on its protease activity toward H3NT. Remarkably, artificial H3NT proteolysis at target gene promoters with dCAS9‐MMP‐9 is sufficient for establishing their transcriptional competence in colon cancer cells, underscoring the importance of MMP‐9‐dependent H3NT proteolysis per se in the transactivation process. Our data establish new functions and mechanisms for MMP‐9 in driving the oncogenic transcription program in colon cancer through H3NT proteolysis, and demonstrate how this epigenetic pathway can be exploited as a potential therapeutic target for cancer treatment.