TRAF6 regulates proliferation of stromal cells in the transition and peripheral zones of benign prostatic hyperplasia via Akt/mTOR signaling

Shi, Yunfeng; Yu, Dian-Jun; Jiang, Chuanwen; Wang, Xing‐Jie; Zhu, Yiping; Zhao, Ruizhe; Lv, Zhong; Sun, Xuejing

doi:10.1002/pros.23456

Cited by 12 publications

(8 citation statements)

References 35 publications

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“…4b), and the subgroup enrichment of mTOR signaling was validated in two independent cohorts (Fig. 4c), consistent with prior isolated reports in model systems 40,41 . To interrogate the potential effect of mTOR treatment on the prostate, we examined prostate size on cross-sectional imaging in patients taking mTOR inhibitors.…”

Section: And 4 Supplementarysupporting

confidence: 89%

Integrative multiplatform molecular profiling of benign prostatic hyperplasia identifies distinct subtypes

Shoag

Poliak

et al. 2020

Nat Commun

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Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is among the most common diseases affecting aging men, but the underlying molecular features remain poorly understood, and therapeutic options are limited. Here we employ a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epigenetic profiling. We find no evidence of neoplastic features in BPH: no evidence of driver genomic alterations, including low coding mutation rates, mutational signatures consistent with aging tissues, minimal copy number alterations, and no genomic rearrangements. At the epigenetic level, global hypermethylation is the dominant process. Integrating transcriptional and methylation signatures identifies two BPH subgroups with distinct clinical features and signaling pathways, validated in two independent cohorts. Finally, mTOR inhibitors emerge as a potential subtype-specific therapeutic option, and men exposed to mTOR inhibitors show a significant decrease in prostate size. We conclude that BPH consists of distinct molecular subgroups, with potential for subtype-specific precision therapy.

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Section: And 4 Supplementarysupporting

confidence: 89%

Integrative multiplatform molecular profiling of benign prostatic hyperplasia identifies distinct subtypes

Shoag

Poliak

et al. 2020

Nat Commun

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“…To nominate potential subtype specific therapeutic options, we utilized the Connectivity Map 40, 41 analysis ( Figure 4A and Table S13), which uses transcriptional expression data to probe relationships between diseases, cell physiology, and therapeutics. Strikingly, we found 50% of nominated compounds in BPH-A subgroup were related to inhibition of mTOR signaling ( Figure 4B), and the subgroup enrichment of mTOR signaling was validated in two independent cohorts ( Figure 4C), consistent with prior isolated reports in model systems 42,43,44 . To interrogate the potential effect of mTOR treatment on the prostate, we examined prostate size on cross-sectional imaging in patients taking mTOR inhibitors.…”

Section: Resultssupporting

confidence: 86%

Integrative genomic, transcriptomic, and epigenomic analyses of benign prostatic hyperplasia reveal new options for therapy

Shoag

Poliak

et al. 2019

Preprint

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Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is one of the most common diseases affecting aging men, but the underlying molecular features of BPH remain poorly understood, and therapeutic options are limited. Here we employed a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epigenetic profiling of 18 BPH cases. At the molecular level, we found no evidence of neoplastic features in BPH: no evidence of driver genomic alterations, including low coding mutation rates, mutational signatures consistent with aging tissues, minimal copy number alterations, and no genomic rearrangements.Similarly at the epigenetic level, we found global hypermethylation was the dominant process (unlike most neoplastic processes). By integrating transcriptional and methylation signatures, we identified two BPH subgroups with distinct clinical features and associated signaling pathways, which were validated in two independent cohorts.Finally, our analyses nominated mTOR inhibitors as a potential subtype-specific therapeutic option. Supporting this, a cohort of men exposed to mTOR inhibitors showed a significant decrease in prostate size. Our results demonstrate that BPH consists of distinct molecular subgroups, with potential for subtype-specific precision therapy via mTOR inhibition.

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“…TRAF6 depends on lysine 63 (K63) to activate ubiquitination [4], and FOXOs' promotion of cell proliferation is regulated by ubiquitin proteasome pathways [32]. TRAF6 was confirmed to regulate stromal cell proliferation through the Akt/mTOR signaling pathway in prostatic hyperplasia [33]. Furthermore, in oral and breast cancers, the underlying molecular mechanism of TRAF6 is the promotion of AKT ubiquitination and phosphorylation [9].…”

Section: Discussionmentioning

confidence: 99%

TRAF6 Promotes Gastric Cancer Cell Self-Renewal, Proliferation, and Migration

Yang

Jin

et al. 2020

Stem Cells International

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Gastric cancer is the third most common type of tumor associated with death. TRAF6 belongs to the tumor necrosis factor receptor-associated factor family and has been demonstrated to be involved in tumor progression in various cancers. However, the exact effect of TRAF6 on gastric cancer stem cells has not been extensively studied. In this study, abnormal expression of TRAF6 was found in gastric cancer tissues. Overexpression of TRAF6 enhanced proliferation and migration, and TRAF6 knockdown reversed this phenomenon in gastric cancer cells. Moreover, TRAF6 may inhibit differentiation and promote stemness and epithelial-mesenchymal transition (EMT). Transcriptome profiles revealed 701 differentially expressed genes in the wild-type group and the TRAF6 knockout group. Potential molecules associated with cell proliferation and migration were identified, including MAPK, FOXO, and IL-17. In conclusion, TRAF6 is a significant factor promoting proliferation and migration in gastric cancer cells and may provide a new target for the accurate treatment of gastric cancer.

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TRAF6 regulates proliferation of stromal cells in the transition and peripheral zones of benign prostatic hyperplasia via Akt/mTOR signaling

Abstract: TRAF6 can promote the proliferation of stromal cells of BPH via Akt/mTOR signaling. Our results may make stromal TRAF6 responsible for zonal characteristic of BPH and as a promising therapeutic strategy for BPH treatment.

Cited by 12 publications

References 35 publications

Integrative multiplatform molecular profiling of benign prostatic hyperplasia identifies distinct subtypes

Integrative multiplatform molecular profiling of benign prostatic hyperplasia identifies distinct subtypes

Integrative genomic, transcriptomic, and epigenomic analyses of benign prostatic hyperplasia reveal new options for therapy

TRAF6 Promotes Gastric Cancer Cell Self-Renewal, Proliferation, and Migration

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