USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses

Zou, Qiang; Jin, Jin; Hu, Hongbo; Li, Haiyan S.; Romano, Simona; Xiao, Yichuan; Nakaya, Masato; Zhou, Xiaofei; Cheng, Xuhong; Yang, Peirong; Lozano, Guillermina; Zhu, Chengming; Watowich, Stephanie S.; Ullrich, Stephen E.; Sun, Shao Cong

doi:10.1038/ni.2885

Cited by 217 publications

(225 citation statements)

References 46 publications

(67 reference statements)

Supporting

Mentioning

210

Contrasting

Order By: Relevance

“…To date, the first well‐studied USP in melanoma was USP13, of which the significant up‐regulation contributed to melanoma growth via deubiquitination and stabilization of melanocyte lineage‐specific transcriptional factor MITF 13. Apart from this, USP8 and USP15 have been reported to act as oncogenic factor in melanoma, highlighting that both ubiquitin‐conjugating and ubiquitin‐deconjugating enzymes played important roles in melanoma tumour biology 31, 32. In the present study, we found that USP4 was another novel oncogene belonging to USP family with integrated effects on inhibiting cell apoptosis and facilitating tumour metastasis, further revealing the close linkage between dysregulated ubiquitination and cancer development.…”

Section: Discussionmentioning

confidence: 99%

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Guo

Pei

et al. 2018

J Cellular Molecular Medi

View full text Add to dashboard Cite

Melanoma is the most malignant skin cancer with increasing incidence worldwide. Although innovative therapies such as BRAF inhibitor and immune checkpoint inhibitor have gained remarkable advances, metastatic melanoma remains an incurable disease for its notorious aggressiveness. Therefore, further clarification of the underlying mechanism of melanoma pathogenesis is critical for the improvement of melanoma therapy. Ubiquitination is an important regulatory event for cancer hallmarks and melanoma development, and the deubiquitinating enzymes including ubiquitin‐specific peptidase (USP) families are greatly implicated in modulating cancer biology. Herein, we first found that the expression of the deubiquitinase USP4 was significantly up‐regulated in melanoma tissues and cell lines. Furthermore, although USP4 knockdown had little impact on melanoma cell proliferation, it could increase the sensitivity to DNA damage agent cisplatin. We subsequently showed that USP4 regulated cisplatin‐induced cell apoptosis via p53 signalling. More importantly, USP4 could accentuate the invasive and migratory capacity of melanoma cells by promoting epithelial‐mesenchymal transition. Altogether, our results demonstrate that the up‐regulated USP4 plays an oncogenic role in melanoma by simultaneously suppressing stress‐induced cell apoptosis and facilitating tumour metastasis.

show abstract

Section: Discussionmentioning

confidence: 99%

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Guo

Pei

et al. 2018

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…For example, MDM2 and PPM1D were among the top 15 candidates. USP15, another validated top candidate, has also been shown to affect p53 levels via MDM2 stabilization (Zou et al 2014). In the E6 sublibrary screen, we identified RHOA, a Rho GTPase protein at the top of the scored gene list that is involved in negatively regulating multiple INK4 family genes, including p16…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports have suggested that some of the validated genes are involved in the p53 or cell cycle regulation. For example, USP15 was shown to stabilize MDM2 to promote p53 degradation (Zou et al 2014), which could explain why it scored. We noticed that the TP53I13 and the DLX6 ORFs appeared to be truncated in the ORFeome library when compared with the NCBI reference sequence; therefore, further analysis of full-length ORFs will be required to elucidate the function of these ORFs in senescence.…”

Section: Validation Of Selected Screen Candidatesmentioning

confidence: 99%

A gain-of-function senescence bypass screen identifies the homeobox transcription factor DLX2 as a regulator of ATM–p53 signaling

Wang

Sack

et al. 2016

Genes Dev.

View full text Add to dashboard Cite

Senescence stimuli activate multiple tumor suppressor pathways to initiate cycle arrest and a differentiation program characteristic of senescent cells. We performed a two-stage, gain-of-function screen to select for the genes whose enhanced expression can bypass replicative senescence. We uncovered multiple genes known to be involved in p53 and Rb regulation and ATM regulation, two components of the CST (CTC1-STN1-TEN1) complex involved in preventing telomere erosion, and genes such as REST and FOXO4 that have been implicated in aging. Among the new genes now implicated in senescence, we identified DLX2, a homeobox transcription factor that has been shown to be required for tumor growth and metastasis and is associated with poor cancer prognosis. Growth analysis showed that DLX2 expression led to increased cellular replicative life span. Our data suggest that DLX2 expression reduces the protein components of the TTI1/TTI2/TEL2 complex, a key complex required for the proper folding and stabilization of ATM and other members of the PIKK (phosphatidylinositol 3-kinase-related kinase) family kinase, leading to reduced ATM-p53 signaling and senescence bypass. We also found that the overexpression of DLX2 exhibited a mutually exclusive relationship with p53 alterations in cancer patients. Our functional screen identified novel players that may promote tumorigenesis by regulating the ATM-p53 pathway and senescence.

show abstract

“…Very recently, USP15 was shown to target MDM2 with effects on the stability of both p53 and the T-cell transcription factor, NFATc. Thus, USP15 inhibition could result in direct tumor cell apoptosis and increased T-cell responsiveness (19).…”

Section: Usp-associated Mutations and Gene Fusions In Hematologic Malmentioning

confidence: 99%

Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer

2014

View full text Add to dashboard Cite

The ubiquitin-proteasome system (UPS) has emerged as a therapeutic focus and target for the treatment of cancer. The most clinically successful UPS-active agents (bortezomib and lenalidomide) are limited in application to hematologic malignancies, with only marginal efficacy in solid tumors. Inhibition of specific ubiquitin E3 ligases has also emerged as a valid therapeutic strategy, and many targets are currently being investigated. Another emerging and promising approach in regulation of the UPS involves targeting deubiquitinases (DUB). The DUBs comprise a relatively small group of proteins, most with cysteine protease activity that target several key proteins involved in regulation of tumorigenesis, apoptosis, senescence, and autophagy. Through their multiple contacts with ubiquitinated protein substrates involved in these pathways, DUBs provide an untapped means of modulating many important regulatory proteins that support oncogenic transformation and progression. Ubiquitin-specific proteases (USP) are one class of DUBs that have drawn special attention as cancer targets, as many are differentially expressed or activated in tumors or their microenvironment, making them ideal candidates for drug development. This review attempts to summarize the USPs implicated in different cancers, the current status of USP inhibitor-mediated pharmacologic intervention, and future prospects for USP inhibitors to treat diverse cancers. Cancer Res; 74(18); 4955-66. Ó2014 AACR.

show abstract

USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses

Cited by 217 publications

References 46 publications

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

A gain-of-function senescence bypass screen identifies the homeobox transcription factor DLX2 as a regulator of ATM–p53 signaling

Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer

Contact Info

Product

Resources

About