Journal
ONCOGENE
Volume 41, Issue 4, Pages 560-570Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-021-02109-5
Keywords
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Funding
- NIH [AR073233, P30CA014089]
- National Cancer Institute
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The study reveals that MMP-9 localizes to the nucleus of melanoma cells and enhances gene expression by proteolytically clipping histone H3 N-terminal tail (H3NT). MMP-9 cooperates functionally with p300/CBP to cleave H3NT in a manner dependent on p300/CBP-mediated acetylation of H3K18.
Melanoma is a type of skin cancer that develops in pigment-producing melanocytes and often spreads to other parts of the body. Aberrant gene expression has been considered as a crucial step for increasing the risk of melanomagenesis, but how chromatin reorganization contributes to this pathogenic process is still not well understood. Here we report that matrix metalloproteinase 9 (MMP-9) localizes to the nucleus of melanoma cells and potentiates gene expression by proteolytically clipping the histone H3 N-terminal tail (H3NT). From genome-wide studies, we discovered that growth-regulatory genes are selectively targeted and activated by MMP-9-dependent H3NT proteolysis in melanoma cells. MMP-9 cooperates functionally with p300/CBP because MMP-9 cleaves H3NT in a manner that is dependent on p300/CBP-mediated acetylation of H3K18. The functional significance of MMP-9-dependent H3NT proteolysis is further underscored by the fact that RNAi knockdown and small-molecule inhibition of MMP-9 and p300/CBP impede melanomagenic gene expression and melanoma tumor growth. Together, our data establish new functions and mechanisms for nuclear MMP-9 in promoting melanomagenesis and demonstrate how MMP-9-dependent H3NT proteolysis can be exploited to prevent and treat melanoma skin cancer.
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