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

Abstract

Outcomes for metastatic Ewing sarcoma and osteosarcoma are dismal and have not changed for decades. Oxidative stress attenuates melanoma metastasis, and melanoma cells must reduce oxidative stress to metastasize. We explored this in sarcomas by screening for oxidative stress sensitizers, which identified the class I HDAC inhibitor MS‐275 as enhancing vulnerability to reactive oxygen species (ROS) in sarcoma cells. Mechanistically, MS‐275 inhibits YB‐1 deacetylation, decreasing its binding to 5′‐UTRs of NFE2L2 encoding the antioxidant factor NRF2, thereby reducing NFE2L2 translation and synthesis of NRF2 to increase cellular ROS. By global acetylomics, MS‐275 promotes rapid acetylation of the YB‐1 RNA‐binding protein at lysine‐81, blocking binding and translational activation of NFE2L2, as well as known YB‐1 mRNA targets, HIF1A, and the stress granule nucleator, G3BP1. MS‐275 dramatically reduces sarcoma metastasis in vivo, but an MS‐275‐resistant YB‐1K81‐to‐alanine mutant restores 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.

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

“…The DNA and RNA binding protein Y-box binding protein 1 (YB-1) binds to NRF2 in response to oxidative stress. Entinostat induces YB-1 acetylation and blocks its binding to NRF2, reducing NRF2 synthesis and increasing ROS levels in sarcoma cells (El-Naggar et al, 2019).…”

Y-Box Binding Proteins in mRNP Assembly, Translation, and Stability Control

“…For some mRNAs, such as that of G3BP1, the data on YB-1 involvement in translational control are contradictive. Some researchers report that YB-1 enhances G3BP1 mRNA translation through binding to the 5 UTR [125,126], while others deny such regulation [127,128]. The difference in conclusions can be explained by the presence or absence of regulatory RBPs whose binding and activity are modulated by YB-1.…”

“…For example, YB-1 phosphorylation at Ser102 promotes the translation of growth-related mRNAs [75,107], while the overexpression of YB-1 is unable to be phosphorylated at Ser102 and promotes the translation of EMT-related genes [144]. YB-1 acetylation at Lys81 prevents HIF-1α and G3BP1 translation activation [125]. An unknown modification of YB-1 (possibly phosphorylation) upon serum or IGF-I stimulation decreases the ability of YB-1 to bind OXPHOS mRNAs (NDUFA9, NDUFB8, SDHB, etc.…”

Tumour Progression Stage-Dependent Secretion of YB-1 Stimulates Melanoma Cell Migration and Invasion

“…On the other hand, YB-1 is capable of inducing a highly motile and invasive mesenchymal phenotype in epithelial tumours such as breast, prostate, and gastric carcinomas, as well as in malignant melanoma and sarcoma [ 17 , 36 , 37 , 38 , 39 ]. In this context, cytoplasmic YB-1 has been shown to promote the translation of mRNAs encoding both epithelial-to-mesenchymal transition (EMT)-regulating (e.g., Snail, Twist, Zeb2/Sip1) and cytoprotective factors facilitating tumour cell metastasis [ 37 , 39 , 40 , 41 , 42 ].…”