MMP-9 drives the melanomagenic transcription program through histone H3 tail proteolysis.
Oncogene
; 41(4): 560-570, 2022 01.
Article
de En
| MEDLINE
| ID: mdl-34785776
ABSTRACT
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Histone
/
Matrix metalloproteinase 9
/
Mélanome
Limites:
Animals
/
Humans
Langue:
En
Journal:
Oncogene
Sujet du journal:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Année:
2022
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique