Abstract
MYC drives the tumorigenesis of human cancers, including prostate cancer (PrCa), thus deubiquitinase (DUB) that maintains high level of c-Myc oncoprotein is a rational therapeutic target. Several ubiquitin-specific protease (USP) family members of DUB have been reported to deubiquitinate c-Myc, but none of them is the physiological DUB for c-Myc in PrCa. By screening all the DUBs, here we reveal that OTUD6A is exclusively amplified and overexpressed in PrCa but not in other cancers, eliciting a prostatic-specific oncogenic role through deubiquitinating and stabilizing c-Myc oncoprotein. Moreover, genetic ablation of OTUD6A efficiently represses prostatic tumorigenesis of both human PrCa cells and the Hi-Myc transgenic PrCa mice, via reversing the metabolic remodeling caused by c-Myc overexpression in PrCa. These results indicate that OTUD6A is a physiological DUB for c-Myc in PrCa setting and specifically promotes prostatic tumorigenesis through stabilizing c-Myc oncoprotein, suggesting that OTUD6A could be a unique therapeutic target for Myc-driven PrCa.
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Data availability
The data that support the findings of this study are available from the corresponding authors upon reasonable request. RNA-seq data discussed in this paper have been deposited in NCBI’s Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE189716.
Change history
19 April 2022
A Correction to this paper has been published: https://doi.org/10.1038/s41418-022-00978-1
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Acknowledgements
We thank Dr. Zhihui Feng, Dr. Jian Ding, and Dr. Yongping Shao for suggestions and comments on this work. We thank Dr. Yong Yang from China Pharmaceutical University for his kind help for providing Hi-Myc mice as gift.
Funding
This work was supported by the National Natural Science Foundation of China [81802787, 31700684, 31870848, 31770917 and 32171102], the National Basic Research Program of China [973 Program 2015CB856302 and 2015CB553602], the China Postdoctoral Science Foundation [2018M643673], and the National Key Research and Development Projects of China [2019YFD1002400].
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The idea was conceived by WW, LZ, JKL, and JGL. YP and JL designed and performed most of the experiments with assistance from ZW, CC, TZ, PG, ZH, HL, YW, JG, and JZ. YP and JL wrote the manuscript. WW, LZ, JKL, and JGL supervised the study and edited the manuscript. All authors commented on the manuscript.
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All animal experiments were approved by the Animal Use and Care Committee of the School of Life Science and Technology, Xi’an Jiaotong University, based on the Guide for the Care and Use of Laboratory Animals: eighth edition (ISBN10: 0-309-15396-4).
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Peng, Y., Liu, J., Wang, Z. et al. Prostate-specific oncogene OTUD6A promotes prostatic tumorigenesis via deubiquitinating and stabilizing c-Myc. Cell Death Differ 29, 1730–1743 (2022). https://doi.org/10.1038/s41418-022-00960-x
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DOI: https://doi.org/10.1038/s41418-022-00960-x
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