Author: Zhou, Qiming ; Kang, Wei ; Pan, Yasi ; Wong, Chi Chun ; Chen, Danyu ; Liang, Cong ; Cheung, Alvin H.-K. ; Wei, Qinyao ; Ji, Fenfen ; Cheung, Henley ; Yu, Jun ; Lau, Harry C.-H. ; Yang, Zhenjie ; Chen, Huarong ; Huang, Pingmei

AbstractThe N6-methyladenosine (m6A) RNA-binding protein YTHDF1 is frequently overexpressed in colorectal cancer and drives chemotherapeutic resistance. To systematically identify druggable targets in colorectal cancer with high expression of YTHDF1, this study used a CRISPR/Cas9 screening strategy that revealed RUVBL1 and RUVBL2 as putative targets. RUVBL1/2 were overexpressed in primary colorectal cancer samples and represented independent predictors of poor patient prognosis. Functionally, loss of RUVBL1/2 preferentially impaired the growth of YTHDF1-high colorectal cancer cells, patient-derived primary colorectal cancer organoids, and subcutaneous xenografts. Mechanistically, YTHFD1 and RUVBL1/2 formed a positive feedforward circuit to accelerate oncogenic translation. YTHDF1 bound to m6A-modified RUVBL1/2 mRNA to promote translation initiation and protein expression. Coimmunoprecipitation and mass spectrometry identified that RUVBL1/2 reciprocally interacted with YTHDF1 at 40S translation initiation complexes. Consequently, RUVBL1/2 depletion stalled YTHDF1-driven oncogenic translation and nascent protein biosynthesis, leading to proliferative arrest and apoptosis. Ribosome sequencing revealed that RUVBL1/2 loss impaired the activation of MAPK, RAS, and PI3K-AKT signaling induced by YTHDF1. Finally, the blockade of RUVBL1/2 by the pharmacological inhibitor CB6644 or vesicle-like nanoparticle-encapsulated siRNAs preferentially arrested the growth of YTHDF1-expressing colorectal cancer in vitro and in vivo. Our findings show that RUVBL1/2 are potential prognostic markers and druggable targets that regulate protein translation in YTHDF1-high colorectal cancer.Significance: RUVBL1/2 inhibition is a therapeutic strategy to abrogate YTHDF1-driven oncogenic translation and overcome m6A dysregulation in colorectal cancer.

01 Jun 2024·Cell Reports Physical Science

Mechanism of allosteric inhibition of RUVBL1-RUVBL2 ATPase by the small molecule CB-6644

Author: Garcia-Martin, Carmen ; Llorca, Oscar ; Boskovic, Jasminka ; Lopez-Perrote, Andres

The RuvB-like protein 1/2 complex (RUVBL1/2) is a hetero-hexameric ATPase essential in several cellular processes, including chromatin remodeling and the assembly of mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2.The aminopyrazolone CB-6644, a small mol. that allosterically inhibits RUVBL1/2, displays antitumor activity in animal models.However, its binding site and mechanism of action are not yet understood.Here, we applied cryoelectron microscopy (cryo-EM) to determine the ∼2.4 Å resolution structure of the RUVBL1/2 complex bound to ATP and CB-6644, which, together with addnl. biochem. and cryo-EM experiments, reveals that ATP binding to RUVBL1/2 induces large conformational changes that CB-6644 recognizes by interacting at the interface between two subunits.CB-6644 traps this ATP-bound conformation and prevents ATP hydrolysis.Interestingly, our results suggest a mechanism that couples the nucleotide state, the conformation of RUVBL1/2 domain II (DII), and the interaction of RUVBL1/2 with other proteins.Our findings reveal how ATP regulates RUVBL1/2 and how this is affected by CB-6644 binding.

03 Jun 2022·OncogeneQ1 · MEDICINE

RUVBL1 promotes enzalutamide resistance of prostate tumors through the PLXNA1-CRAF-MAPK pathway

Q1 · MEDICINE

Article

Author: Yu, Zeyuan ; Han, Bo ; Zhao, Ru ; Hu, Jing ; Zhang, Wenbo ; Jia, Wenqiao ; Wang, Xueli ; Shao, Yang ; Feng, Tingting ; Liu, Hui ; Wang, Xinpei ; Wang, Xin ; Dou, Baokai ; Sun, Feifei ; Liu, Kaihua ; Gao, Lin ; Dong, Xuesen ; Liu, Junmei

Although enzalutamide improves the overall survival of patients with metastatic prostate cancers, enzalutamide resistance (ENZR) will be inevitably developed. Emerging evidence support that alternative oncogenic pathways may bypass the androgen receptor (AR) signaling to promote ENZR progression, however, the underpinning mechanisms remain poorly defined. Here, we report that the expression of RuvB like AAA ATPase 1 (RUVBL1) is upregulated in ENZR cells and xenograft models and prostate tumors in patients. Enzalutamide increases RUVBL1 accumulation in the cytoplasm, which in turn enhances the recruitment of CRAF proto-oncogene serine/threonine kinase protein to plexin A1 (PLXNA1) and the subsequent activation of the downstream MAPK pathway. Co-overexpression of RUVBL1 and PLXNA1 defines a subgroup of prostate cancer (PCa) patients with a poor prognosis. Furthermore, pharmacological inhibition of RUVBL1 by CB-6644 suppresses ENZR cell proliferation and xenograft growth and allows re-sensitization of ENZR cells and xenografts to enzalutamide, indicating that RUVBL1 may act to substitute the AR signaling to promote cancer cell survival and ENZR development. Together, these findings may lead to the identification of RUVBL1 as a potential therapeutic target for ENZR tumors.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	United States	Cleave Therapeutics, Inc.	14 Jan 2019

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