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

ABSTRACT: Outcomes for metastatic bone sarcomas, Ewing sarcoma and osteosarcoma, are dismal and remain unchanged for decades. Oxidative stress attenuates melanoma metastasis, and melanoma cells must reduce oxidative stress to metastasize. To explore this in sarcomas, we screened libraries of approved compounds for agents sensitizing sarcoma cells to oxidative stress. This identified the class I HDAC inhibitor MS-275 as enhancing sensitivity to reactive oxygen species (ROS). Mechanistically, MS-275 inhibits YB-1 deacetylation, decreasing physical binding between YB-1 and the 5UTR of NFE2L2, thereby non-transcriptionally reducing translation and expression of the master antioxidant factor, NRF2, which reduces cellular ROS. Indeed, global acetylomics revealed that MS-275 promotes rapid acetylation of the YB-1 RNA binding protein at lysine-81, blocking RNA binding and translational activation of NFE2L2, encoding NRF2, as well as known YB-1 mRNA targets, HIF1A and the stress granule nucleator, G3BP1. MS-275 dramatically reduced sarcoma metastasis in vivo, but an MS-275-resistant YB-1 K81-to-alanine (K81A) mutant restored metastatic capacity and NRF2, HIF1α, and G3BP1 synthesis in MS-275 treated mice. These studies describe a novel function for MS-275 through enhanced YB-1 acetylation, thus inhibiting YB-1 translational control of key cytoprotective factors and its pro-metastatic activity.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Bone Osteosarcoma

SUBMITTER: Gian Luca Negri  

LAB HEAD: Gregg B. Morin

PROVIDER: PXD014827 | Pride | 2019-10-28

REPOSITORIES: Pride