MMP-9 drives the melanomagenic transcription program through histone H3 tail proteolysis.

Yonghwan Shin, Sungmin Kim, Nikhil B Ghate, Suhn K Rhie, Woojin An

Oncogene 2022 Jan

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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. © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Citation

Yonghwan Shin, Sungmin Kim, Nikhil B Ghate, Suhn K Rhie, Woojin An. MMP-9 drives the melanomagenic transcription program through histone H3 tail proteolysis. Oncogene. 2022 Jan;41(4):560-570