Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1‐EEF1A1 Axis

Abstract

Epigenetic dysregulation is reported in multiple cancers including Ewing sarcoma (EwS). However, the epigenetic networks underlying the maintenance of oncogenic signaling and therapeutic response remain unclear. Using a series of epigenetics-and complex-focused CRISPR screens, RUVBL1, the ATPase component of NuA4 histone acetyltransferase complex, is identified to be essential for EwS tumor progression. Suppression of RUVBL1 leads to attenuated tumor growth, loss of histone H4 acetylation, and ablated MYC signaling. Mechanistically, RUVBL1 controls MYC chromatin binding and modulates the MYC-driven EEF1A1 expression and thus protein synthesis. High-density CRISPR gene body scan pinpoints the critical MYC interacting residue in RUVBL1. Finally, this study reveals the synergism between RUVBL1 suppression and pharmacological inhibition of MYC in EwS xenografts and patient-derived samples. These results indicate that the dynamic interplay between chromatin remodelers, oncogenic transcription factors, and protein translation machinery can provide novel opportunities for combination cancer therapy.

Ruvbl1 is required for the reproduction of the corn planthopper,Peregrinus maidis

“…Our findings further extend Ruvbl1 functions as a putative regulator of P. maidis reproduction. It is well established that Ruvbl1 plays multiple roles involved in cell development and proliferation and modulating its activity by either depletion or overexpression can lead to several cellular developmental abnormalities such as arrested larval development, cellular death, cancer and others (Bellosta et al, 2005, Jha and Dutta, 2009, Wang et al, 2018, Li et al, 2023. Our results suggest that PmRuvbl1 silencing likely affected P. maidis fecundity at different stages of the reproductive process.…”

Tumor heterogeneity and tumor-microglia interactions in primary and recurrent IDH1-mutant gliomas

“…Our results reveal an enriched MYC/MYCN regulon within the RE population, suggesting increased biosynthetic properties due to the known targeting of EEF1A1 by MYC. 37 The combined analysis of single-nuclei and IHC data consistently demonstrated a higher RE prevalence in oligodendrogliomas compared with astrocytomas. Deconvolution of bulk RNA-seq datasets corroborated this finding, suggesting a widespread expression of the RE population in nearly all oligodendrogliomas.…”

Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2

“…Next, we aimed to map the domains that mediate the interaction with MYC on RUVBL1 to generate interaction-deficient mutants of RUVBL1. Based on a recent report in Ewing sarcoma, 54 we designed a series of putative loss-of-interaction mutants for RUVBL1 (RUVBL1 Δ94-118 , RUVBL1 Δ102-107 , RUVBL1 K108A ) and tested their interaction in co-immunoprecipitation experiments in KPC cells. Both RUVBL1 mutants lacking the loop in the central channel of the RUVBL1/2 hexamer (RUVBL1 Δ94-118 , RUVBL1 Δ102-107 ) lost the ability to bind MYC (online supplemental figure S5H) and could not rescue the growth defect caused by auxin-mediated loss of endogenous RUVBL1 (online supplemental figure S5I).…”