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

Shin, Yonghwan; Kim, Sungmin; Ghate, Nikhil Baban; Rhie, Suhn Kyong; An, Woojin

doi:10.1038/s41388-021-02109-5

Cited by 18 publications

(29 citation statements)

References 45 publications

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“…Although these reports predicted that the MMP-2 target genes in U2OS cells would be downregulated following depletion of MMP-2 and H3NT proteolysis, there were only slightly more MMP-2 target genes that were downregulated (57%) than upregulated (43%). Interestingly, these findings were consistent with other reports where the proportions of differentially expressed genes in melanoma cells and lymphoma-derived monocytes following depletion of H3NT proteolysis were strikingly similar, with 57% of genes downregulated and 43% upregulated [ 19 , 32 ]. These collective findings suggest that the establishment of H3NT proteolysis at lineage-specifying genes is necessary for their activation and proficient terminal differentiation, whereas H3NT proteolysis plays a minor role in the maintenance of target gene expression in proliferating cancer cells.…”

Section: Discussionsupporting

confidence: 92%

The MMP-2 histone H3 N-terminal tail protease is selectively targeted to the transcription start sites of active genes

Weekley

Rice

2023

Epigenetics & Chromatin

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Background Proteolysis of the histone H3 N-terminal tail (H3NT) is an evolutionarily conserved epigenomic feature of nearly all eukaryotes, generating a cleaved H3 product that is retained in ~ 5–10% of the genome. Although H3NT proteolysis within chromatin was first reported over 60 years ago, the genomic sites targeted for H3NT proteolysis and the impact of this histone modification on chromatin structure and function remain largely unknown. The goal of this study was to identify the specific regions targeted for H3NT proteolysis and investigate the consequence of H3NT “clipping” on local histone post-translational modification (PTM) dynamics. Results Leveraging recent findings that matrix metalloproteinase 2 (MMP-2) functions as the principal nuclear H3NT protease in the human U2OS osteosarcoma cell line, a ChIP-Seq approach was used to map MMP-2 localization genome wide. The results indicate that MMP-2 is selectively targeted to the transcription start sites (TSSs) of protein coding genes, primarily at the + 1 nucleosome. MMP-2 localization was exclusive to highly expressed genes, further supporting a functional role for H3NT proteolysis in transcriptional regulation. MMP-2 dependent H3NT proteolysis at the TSSs of these genes resulted in a > twofold reduction of activation-associated histone H3 PTMs, including H3K4me3, H3K9ac and H3K18ac. One of genes requiring MMP-2 mediated H3NT proteolysis for proficient expression was the lysosomal cathepsin B protease (CTSB), which we discovered functions as a secondary nuclear H3NT protease in U2OS cells. Conclusions This study revealed that the MMP-2 H3NT protease is selectively targeted to the TSSs of active protein coding genes in U2OS cells. The resulting H3NT proteolysis directly alters local histone H3 PTM patterns at TSSs, which likely functions to regulate transcription. MMP-2 mediated H3NT proteolysis directly activates CTSB, a secondary H3NT protease that generates additional cleaved H3 products within chromatin.

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Section: Discussionsupporting

confidence: 92%

The MMP-2 histone H3 N-terminal tail protease is selectively targeted to the transcription start sites of active genes

Weekley

Rice

2023

Epigenetics & Chromatin

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“…Under MMP-2 inhibition, there is minimal, or a lack of, histone H3 cleavage, and this results in a reduction in transcription, as well as cell proliferation [ 27 ]. Another study also found that MMP-9 (Gelatinase-B, closely related to MMP-2) is able to clip histone H3 and regulate gene expression involved in melanoma formation [ 132 ]. These studies further support MMP-2’s involvement in the epigenetic regulation of gene transcription within not only the nucleolus, but moreover, the nucleus.…”

Section: Novel Role In Ribosomal Rna Transcriptionmentioning

confidence: 99%

Novel Roles of MT1-MMP and MMP-2: Beyond the Extracellular Milieu

Maybee

Ink

Ali

2022

IJMS

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Matrix metalloproteinases (MMPs) are critical enzymes involved in a variety of cellular processes. MMPs are well known for their ability to degrade the extracellular matrix (ECM) and their extracellular role in cell migration. Recently, more research has been conducted on investigating novel subcellular localizations of MMPs and their intracellular roles at their respective locations. In this review article, we focus on the subcellular localization and novel intracellular roles of two closely related MMPs: membrane-type-1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2). Although MT1-MMP is commonly known to localize on the cell surface, the protease also localizes to the cytoplasm, caveolae, Golgi, cytoskeleton, centrosome, and nucleus. At these subcellular locations, MT1-MMP functions in cell migration, macrophage metabolism, invadopodia development, spindle formation and gene expression, respectively. Similar to MT1-MMP, MMP-2 localizes to the caveolae, mitochondria, cytoskeleton, nucleus and nucleolus and functions in calcium regulation, contractile dysfunction, gene expression and ribosomal RNA transcription. Our particular interest lies in the roles MMP-2 and MT1-MMP serve within the nucleus, as they may provide critical insights into cancer epigenetics and tumor migration and invasion. We suggest that targeting nuclear MT1-MMP or MMP-2 to reduce or halt cell proliferation and migration may lead to the development of new therapies for cancer and other diseases.

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“…We also found that nucleolar MMP-2 activity regulates RNA transcription through the clipping of histone H3, as H3 cleavage is associated with increased ribosomal RNA transcription and minimal or absence of H3 cleavage, when MMP-2 is inhibited, results in reduction in transcription, as well as cell proliferation [87]. Another study also found that MMP-9 (Gelatinase-B, closely related to MMP-2) is able to clip histone H3 and regulates genes expression involved in melanoma formation [88]. These studies further support MMP-2's involvement in epigenetics regulation of genes transcription within not only the nucleolus, but more, the nucleus.…”

Section: Novel Roles Of Mmp-2 Inside Cellsmentioning

confidence: 98%

Novel Roles of MT1-MMP and MMP-2: Beyond the Extracellular Milieu

Maybee¹,

Ink²,

Ali³

2022

Preprint

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Matrix metalloproteinases (MMPs) are critical enzymes involved in a variety of cellular processes. MMPs are well known for their ability to degrade the extracellular matrix (ECM) and their extracellular role in cell migration. Recently, more research has been conducted on investigating novel subcellular localizations of MMPs and their intracellular roles at the respective locations. In this review article, we focus on the subcellular localization and novel intracellular roles of two MMPs closely related: membrane-type-1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2). Although MT1-MMP is commonly known to localize on the cell surface, the protease also localizes to the cytoplasm, caveolae, Golgi, cytoskeleton, centrosome, and nucleus. At these subcellular locations, MT1-MMP functions in cell migration, macrophage metabolism, invadopodia development, spindle formation and genes expression, respectively. Similar to MT1-MMP, MMP-2 localizes to the caveolae, mitochondria, cytoskeleton, nucleus and nucleolus, and functions in calcium regulation, contractile dysfunction, genes expression and ribosomal RNA transcription. Our particular interest lies in the role MMP-2 and MT1-MMP serve within the nucleus, as it may provide critical insights into cancer epigenetics and tumor migration and invasion. We suggest that targeting nuclear MT1-MMP or MMP-2 to reduce or halt cell proliferation and migration may lead to the development of new therapies in cancer and other diseases.

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

Cited by 18 publications

References 45 publications

The MMP-2 histone H3 N-terminal tail protease is selectively targeted to the transcription start sites of active genes

The MMP-2 histone H3 N-terminal tail protease is selectively targeted to the transcription start sites of active genes

Novel Roles of MT1-MMP and MMP-2: Beyond the Extracellular Milieu

Novel Roles of MT1-MMP and MMP-2: Beyond the Extracellular Milieu

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