Loss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer

Li, Xiaoling; Wang, Yunguan; Deng, Su; Zhu, Guanbao; Wang, Choushi; Johnson, Nickolas A.; Zhang, Zeda; Tirado, Carla Rodriguez; Xu, Yaru; Metang, Lauren A.; Gonzalez, Julisa; Mukherji, Atreyi; Ye, Jianfeng; Yang, Yuqiu; Wei, Peng; Tang, Yitao; Hofstad, Mia; Xie, Zhiqun; Yoon, Heewon; Chen, Liping; Liu, Xihui; Chen, Sujun; Zhu, Hong; Strand, Douglas W.; Liu, Han; Raj, Ganesh V.; He, Housheng Hansen; Mendell, Joshua T.; Li, Bo; Wang, Tao; Mu, Ping

doi:10.1016/j.ccell.2023.06.010

Cited by 14 publications

(30 citation statements)

References 169 publications

(140 reference statements)

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“…Despite the initial success of second-generation antiandrogens in treating PCa, unavoidable resistance emerges and significantly impairs patient outcomes [ 6 ]. Using an advanced ranking algorithm, MAGeCK, we re-analyzed our dataset from an in vivo library screen that identified genomic aberrations correlated with resistance [ 24 ]. Our analysis pointed to the depletion of ubiquitin-conjugating enzyme E2 J1 (UBE2J1) as a top candidate associated with antiandrogen (enzalutamide) resistance [ 24 ].…”

Section: Resultsmentioning

confidence: 99%

UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance

Rodriguez Tirado,

Wang,

et al. 2023

Oncogene

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Prostate cancer (PCa) is primarily driven by aberrant Androgen Receptor (AR) signaling. Although there has been substantial advancement in antiandrogen therapies, resistance to these treatments remains a significant obstacle, often marked by continuous or enhanced AR signaling in resistant tumors. While the dysregulation of the ubiquitination-based protein degradation process is instrumental in the accumulation of oncogenic proteins, including AR, the molecular mechanism of ubiquitination-driven AR degradation remains largely undefined. We identified UBE2J1 as the critical E2 ubiquitin-conjugating enzyme responsible for guiding AR ubiquitination and eventual degradation. The absence of UBE2J1, found in 5–15% of PCa patients, results in disrupted AR ubiquitination and degradation. This disruption leads to an accumulation of AR proteins, promoting resistance to antiandrogen treatments. By employing a ubiquitination-based AR degrader to adeptly restore AR ubiquitination, we reestablished AR degradation and inhibited the proliferation of antiandrogen-resistant PCa tumors. These findings underscore the fundamental role of UBE2J1 in AR degradation and illuminate an uncharted mechanism through which PCa maintains heightened AR protein levels, fostering resistance to antiandrogen therapies.

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Section: Resultsmentioning

confidence: 99%

UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance

Rodriguez Tirado,

Wang,

et al. 2023

Oncogene

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“…At the regional scale, APOBEC3 mutagenesis is more pronounced in tissue-specific open-chromatin regions (50,51), indicating that the SGMs preferentially occur in actively expressed genes in which LOF mutations are more likely to have functional consequences. Last, mutational processes that generate SGMs and cause increased tumor heterogeneity may be reined in through therapeutic APOBEC3 inhibition (52), especially as APOBEC3 activity later in tumor evolution has been linked to subclonal diversification, driver mutations, and resistance to targeted therapy (39,53,54).…”

Section: Discussionmentioning

confidence: 99%

Mutational processes of tobacco smoking and APOBEC activity generate protein-truncating mutations in cancer genomes

Adler,

Bahcheli,

Cheng

et al. 2023

Sci. Adv.

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Mutational signatures represent a genomic footprint of endogenous and exogenous mutational processes through tumor evolution. However, their functional impact on the proteome remains incompletely understood. We analyzed the protein-coding impact of single-base substitution (SBS) signatures in 12,341 cancer genomes from 18 cancer types. Stop-gain mutations (SGMs) (i.e., nonsense mutations) were strongly enriched in SBS signatures of tobacco smoking, APOBEC cytidine deaminases, and reactive oxygen species. These mutational processes alter specific trinucleotide contexts and thereby substitute serines and glutamic acids with stop codons. SGMs frequently affect cancer hallmark pathways and tumor suppressors such as TP53 , FAT1 , and APC . Tobacco-driven SGMs in lung cancer correlate with smoking history and highlight a preventable determinant of these harmful mutations. APOBEC-driven SGMs are enriched in YTCA motifs and associate with APOBEC3A expression. Our study exposes SGM expansion as a genetic mechanism by which endogenous and carcinogenic mutational processes directly contribute to protein loss of function, oncogenesis, and tumor heterogeneity.

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“…Its ability to regulate the stability of proteins that drive cancer growth and survival indicates its potential as a therapeutic target. Among the UPS components, ubiquitin-conjugating enzymes, such as ubiquitin-conjugating enzyme E2 J1 (UBE2J1) [ 2 ], have emerged as key players in cancer dynamics, especially in prostate cancer (PCa) where therapy resistance is a significant challenge.…”

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confidence: 99%

“…In our recent study, through a comprehensive in vivo library screening [ 2 ], we have identified the role of UBE2J1 in PCa, particularly its involvement in the degradation of the androgen receptor (AR) [ 3 ]. AR is a key oncogenic driver of PCa growth, making AR-targeted therapies like enzalutamide and abiraterone fundamental to current treatment strategies.…”

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confidence: 99%

“…Resistance to antiandrogen therapy in PCa remains a significant challenge in the management of this deadly disease [ 4 ]. The known mechanisms responsible for this resistance includes increased tumor heterogeneity [ 5 ], lineage plasticity [ 6 , 7 ], mutagenesis and genomic alterations [ 2 ], epigenetic rewiring [ 8 ], and the complex interactions within the tumor microenvironment [ 9 , 10 ]. Despite these variables, approximately 50% of patients resistant to treatment exhibit restored AR signaling.…”

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confidence: 99%

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Restoring our ubiquitination machinery to overcome resistance in cancer therapy

Li,

2024

Oncoscience

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Loss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer

Cited by 14 publications

References 169 publications

UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance

UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance

Mutational processes of tobacco smoking and APOBEC activity generate protein-truncating mutations in cancer genomes

Restoring our ubiquitination machinery to overcome resistance in cancer therapy

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