Class I HDAC inhibitors enhance YB-1 acetylation and oxidative stress to block sarcoma metastasis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metastasis Research

Background:

• Metastatic Ewing sarcoma and osteosarcoma have poor prognoses with limited treatment advancements.
• Oxidative stress is known to inhibit melanoma metastasis, suggesting a similar vulnerability may exist in sarcomas.

Purpose of the Study:

• To identify agents that sensitize sarcoma cells to oxidative stress.
• To elucidate the molecular mechanisms by which MS-275 affects sarcoma metastasis.

Main Methods:

• Screening for oxidative stress sensitizers in sarcoma cells.
• Utilizing class I HDAC inhibitor MS-275.
• Investigating the role of Y-box binding protein 1 (YB-1) acetylation and its targets.
• Employing global acetylomics and in vivo metastasis models.

Main Results:

• MS-275 enhances sarcoma cell vulnerability to reactive oxygen species (ROS).
• MS-275 inhibits YB-1 deacetylation, reducing NRF2 translation and increasing ROS.
• MS-275 blocks YB-1 binding to NFE2L2, HIF1A, and G3BP1 mRNA.
• MS-275 significantly reduces sarcoma metastasis in vivo, which is reversed by a resistant YB-1 mutant.

Conclusions:

• MS-275 exhibits anti-metastatic effects in sarcomas by promoting YB-1 acetylation.
• This acetylation inhibits YB-1's translational control of cytoprotective factors, including NRF2, HIF1α, and G3BP1.
• Targeting YB-1 acetylation represents a novel therapeutic strategy against sarcoma metastasis.