The Regulation of Tumor Suppressor p63 by the Ubiquitin-Proteasome System

Armstrong, S.R.; Wu, Hong; Wang, Benfan; Abuetabh, Yasser; Sergi, Consolato; Leng, Roger

doi:10.3390/ijms17122041

Cited by 37 publications

(35 citation statements)

References 105 publications

(181 reference statements)

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“…Our results revealed that ΔNp63 protein level decreased without significant alteration in mRNA, indicating ΔNp63 might be regulated at the posttranslational level such as ubiquitination. ΔNp63 is targeted by multiple E‐3 ligases such as WWP1, HDM2, FBXW7, Itch, and Pirh2, for ubiquitination and proteasome‐mediated degradation, which acts as new key regulators of the P63 protein . In our results, MG132 attenuated the downregulation of ΔNp63 and ubiquitination level of ΔNp63 increased significantly when cells treated with metformin or/and 4SC‐202 in OSCC.…”

Section: Discussionsupporting

confidence: 58%

“…by multiple E-3 ligases such as WWP1, HDM2, FBXW7, Itch, and Pirh2, for ubiquitination and proteasome-mediated degradation, which acts as new key regulators of the P63 protein. 47,48 In our results, MG132 attenuated the downregulation of ΔNp63 and ubiquitination level of ΔNp63 increased significantly when cells treated with metformin or/and 4SC-202 in OSCC. Furthermore, we examined the ubiquitination level of ΔNp63 under metformin and 4SC-202 treatment with or without MG132, as the results revealed, MG132 treatment increased the ubiquitination level of ΔNp63 under metformin and 4SC-202 treatment.…”

Section: Discussionsupporting

confidence: 54%

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Metformin and 4SC‐202 synergistically promote intrinsic cell apoptosis by accelerating ΔNp63 ubiquitination and degradation in oral squamous cell carcinoma

Tai

Deng

et al. 2019

Cancer Medicine

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Oral squamous cell carcinoma (OSCC) is the most common and aggressive epithelial tumor in the head and neck region with a rising incidence. Despite the advances in basic science and clinical research, the overall survival rate of OSCC remains low. Thus finding novel effective therapeutic agents for OSCC is necessary. In this study, we investigated the effects and mechanisms of combined metformin and 4SC‐202 in OSCC. Our results showed that metformin and 4SC‐202 synergistically suppressed the proliferation and promoted the intrinsic apoptosis of OSCC cells in vitro and in vivo. Importantly, the proteasome inhibitor MG132 impeded the ΔNp63‐decreasing effects after metformin and 4SC‐202 treatment, indicating that metformin and 4SC‐202 could promote the degradation of ΔNp63 protein. Moreover, ubiquitination level of ΔNp63 increased after metformin or/and 4SC‐202 administration. Furthermore, we revealed that ΔNp63 mediated anticancer effects of metformin and 4SC‐202, as overexpression or suppression of ΔNp63 could attenuate or facilitate the apoptosis rate of OSCC under metformin or/and 4SC‐202 treatment. Collectively, metformin and 4SC‐202 synergistically promote intrinsic apoptosis through accelerating ubiquitin‐mediated degradation of ΔNp63 in OSCC, and this co‐treatment can serve as a potential therapeutic scheme for OSCC.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionsupporting

confidence: 54%

Metformin and 4SC‐202 synergistically promote intrinsic cell apoptosis by accelerating ΔNp63 ubiquitination and degradation in oral squamous cell carcinoma

Tai

Deng

et al. 2019

Cancer Medicine

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“…5), we determined that PTPN14 loss results in a downregulation of several markers of epidermal cell differentiation. Consistent with this idea, PTPN14 appears to be a target of regulation by p53 in mouse cells but is likely a p63 target in human cells (79,(86)(87)(88). p63 is a master regulator of epidermal development (89).…”

Section: Discussionmentioning

confidence: 72%

PTPN14 degradation by high-risk human papillomavirus E7 limits keratinocyte differentiation and contributes to HPV-mediated oncogenesis

Hatterschide

Bohidar

Grace

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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High-risk human papillomavirus (HPV) E7 proteins enable oncogenic transformation of HPV-infected cells by inactivating host cellular proteins. High-risk but not low-risk HPV E7 target PTPN14 for proteolytic degradation, suggesting that PTPN14 degradation may be related to their oncogenic activity. HPV infects human keratinocytes but the role of PTPN14 in keratinocytes and the consequences of PTPN14 degradation are unknown. Using an HPV16 E7 variant that can inactivate retinoblastoma tumor suppressor (RB1) but cannot degrade PTPN14, we found that high-risk HPV E7-mediated PTPN14 degradation impairs keratinocyte differentiation. Deletion of PTPN14 from primary human keratinocytes decreased keratinocyte differentiation gene expression. Related to oncogenic transformation, both HPV16 E7-mediated PTPN14 degradation and PTPN14 deletion promoted keratinocyte survival following detachment from a substrate. PTPN14 degradation contributed to high-risk HPV E6/E7-mediated immortalization of primary keratinocytes and HPV + but not HPV − cancers exhibit a gene-expression signature consistent with PTPN14 inactivation. We find that PTPN14 degradation impairs keratinocyte differentiation and propose that this contributes to high-risk HPV E7-mediated oncogenic activity independent of RB1 inactivation.H uman papillomaviruses (HPVs) are nonenveloped, doublestranded DNA viruses that infect and replicate in the stratified squamous epithelium. HPV initially infects keratinocytes in the basal, proliferative layer of the epithelium, and subsequent steps in the HPV replicative cycle-including viral genome amplification, encapsidation, and egress-are dependent on keratinocyte differentiation (1-3). However, HPV genome amplification also requires components of the cellular machinery for DNA replication that are not expressed in differentiating cells. Thus, productive HPV infection must uncouple proliferation and differentiation in the epithelium. Infection with one of the 13-15 "high-risk" HPVs causes nearly all cervical cancer, some other anogenital cancer, and an increasing proportion of HPV + head and neck squamous cell carcinomas (HNSCC) (4-6). In total, HPV infection causes ∼5% of cancers worldwide.The high-risk HPV E7 oncoprotein is able to immortalize human keratinocytes and the efficiency of immortalization is increased by high-risk HPV E6 (7-9). A well-characterized activity of many HPV E7 is to bind and inactivate the retinoblastoma tumor suppressor (RB1) via the LxCxE motif present in HPV E7 conserved region 2 (10-12). In addition, HPV16 E7 can direct the proteasome-mediated degradation of RB1 (13-16). RB1 inactivation releases the inhibition of E2F transcription factors (TF), thus allowing cell cycle progression and acting as a major driver of proliferation. HPV E7 also promotes proliferation by inhibiting the CDK inhibitors p21 WAF1/CIP1 and p27 . In addition to promoting proliferation, transcriptional studies indicate that human cells harboring high-risk HPV genomes express lower levels of differentiation marker genes and that...

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“…Modulation of their abundance by targeting mechanisms that control protein stability presents a viable option (Liu et al, 2015; Wang et al, 2018). ΔNp63 is tightly regulated by the ubiquitin-proteasome-system and ubiquitylated by various E3-ligases (Armstrong et al, 2016). In a tumour, this mechanism is frequently non-functional, leading to the accumulation of ΔNp63 protein (Ruiz et al, 2019) and results of the current study).…”

Section: Discussionmentioning

confidence: 99%

The USP28-ΔNp63 axis is a vulnerability of squamous tumours

Prieto-Garcia

Hartmann

Reissland

et al. 2019

Preprint

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AbstractThe transcription factor ΔNp63 is a master regulator that establishes epithelial cell identity and is essential for the survival of SCC of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ΔNp63 protein and maintains elevated ΔNP63 levels in SCC by counteracting its proteasome-mediated degradation. Interference with USP28 activity by genetic means abolishes the transcriptional identity of SCC cells and suppresses growth and survival of human SCC cells. CRISPR/Cas9-engineered mouse models establish that both induction and maintenance of lung SCC strictly depend on endogenous USP28. Targeting ΔNp63 protein abundance in SCC via inhibition of USP28 therefore is a feasible strategy for the treatment of SCC tumours.SignificanceSCC depend on ΔNp63, and its protein abundance is tightly controlled by the ubiquitin proteasome system. Here, we demonstrate the dependence of SCC on USP28 for various human SCC in vitro and in vivo using murine lung tumour models. As inhibitors for deubiquitylases become available, targeting USP28 is a promising therapeutic strategy.

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The Regulation of Tumor Suppressor p63 by the Ubiquitin-Proteasome System

Cited by 37 publications

References 105 publications

Metformin and 4SC‐202 synergistically promote intrinsic cell apoptosis by accelerating ΔNp63 ubiquitination and degradation in oral squamous cell carcinoma

Metformin and 4SC‐202 synergistically promote intrinsic cell apoptosis by accelerating ΔNp63 ubiquitination and degradation in oral squamous cell carcinoma

PTPN14 degradation by high-risk human papillomavirus E7 limits keratinocyte differentiation and contributes to HPV-mediated oncogenesis

The USP28-ΔNp63 axis is a vulnerability of squamous tumours

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