ZNF213 negatively controls triple negative breast cancer progression via Hippo/YAP signaling

Liu, Yun; Su, Peng; Zhao, Wuchen; Li, Xin; Xiao, Yang; Fan, Jianing; Yang, Huijie; Yan, CH; Mao, Lanzhi; Ding, Youming; Zhu, Jian; Niu, Zhiguo; Zhuang, Ting

doi:10.1111/cas.14916

Cited by 8 publications

(12 citation statements)

References 41 publications

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“…In previous studies, we characterized several E3 ubiquitin ligases involved in modulating Hippo signaling effectors and cancer progression, such as RNF187 and ZNF213 [ 20 , 24 ]. However, protein stability is controlled by the balance between ubiquitination and deubiquitination.…”

Section: Discussionmentioning

confidence: 99%

“…Disrupted regulation of protein ubiquitination could contribute to several human diseases, including cancers [19]. We and other groups discovered several E3 ubiquitin ligases that exert their effects on Hippo pathway effectors and modulate Hippo signaling activity and cancer progression [20][21][22][23][24][25]. Although there are studies reporting the involvement of several deubiquitinases in modulating Hippo signaling, it is still largely unclear which of these deubiquitinases exerts important impacts on Hippo signaling.…”

Section: Introductionmentioning

confidence: 99%

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DUB1 suppresses Hippo signaling by modulating TAZ protein expression in gastric cancer

Wang

et al. 2022

J Exp Clin Cancer Res

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Background The Hippo pathway functions as a tumor suppressor pathway in human cancers, while dysfunction of the Hippo pathway is frequently observed in malignancies. Although YAP/TAZ activity is tightly controlled by the phosphorylation cascade of the MST-LATS-YAP/TAZ axis, it is still unclear why the YAP/TAZ proteins are activated in human cancers despite Hippo pathway activation. Recent studies have suggested that in addition to phosphorylation, several other posttranslational modifications, including ubiquitination, also play critical roles in modulating TAZ function. Methods We used several gastric cancer cell lines and performed western blot analysis, real-time PCR, immunoprecipitation assays, and in vitro ubiquitination assays and established a xenograft mouse model. Results Here, by screening a DUB (deubiquitinase) siRNA library, we discovered that DUB1 functions as a critical modulator that facilitates gastric cancer stemness and progression by deubiquitinating and activating the TAZ protein. We also found that DUB1 expression was elevated in gastric cancer and that elevated DUB1 expression correlated with TAZ activation and poor survival. DUB1 associates with the TAZ protein and deubiquitinates TAZ at several lysine residues, which subsequently stabilizes TAZ and facilitates its function. Conclusions Our study revealed a novel deubiquitinase in the Hippo/TAZ axis and identified one possible therapeutic target for Hippo-driven gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DUB1 suppresses Hippo signaling by modulating TAZ protein expression in gastric cancer

Wang

et al. 2022

J Exp Clin Cancer Res

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“…Ubiquitination, one of the most essential posttranslational modifications (PTMs), has been reported to have implicationse in a wide range of crucial cellular biological processes including signal transduction (Ben‐Dov et al, 2014; Zhou et al, 2021). In organisms, several important signaling pathways such as Wnt (Novellasdemunt et al, 2020; Shen et al, 2021), nuclear factor kappa B (Azuma et al, 2021), and Hippo (Liu et al, 2021) are regulated by ubiquitin ligase‐mediated ubiquitination in different cellular processes. Similar to other PTMs, such as phosphorylation and acetylation, protein ubiquitination is also a reversible process.…”

Section: Introductionmentioning

confidence: 99%

TGFBR2 is a novel substrate and indirect transcription target of deubiquitylase USP9X in granulosa cells

Yang

Wang

Pan

et al. 2022

Journal Cellular Physiology

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The ubiquitin‐specific peptidase 9 X‐linked (USP9X) is one of the highly conserved members belonging to the ubiquitin‐specific proteases (USPs) family, which has been reported to control substrates‐mediated biological functions through deubiquitinating and stabilizing substrates. Here, we have found that TGFBR2, the type II receptor of the transforming growth factor beta (TGF‐β) signaling pathway, is a novel substrate and indirect transcription target of deubiquitylase USP9X in granulosa cells (GCs). Mechanically, USP9X positively influences the expression of TGFBR2 at different levels through two independent ways: (i) directly targets and deubiquitinates TGFBR2, which maintains the protein stability of TGFBR2 through avoiding degradation mediated by ubiquitin‐proteasome system; (ii) indirectly maintains TGFBR2 messenger RNA (mRNA) expression via SMAD4/miR‐143 axis. Specifically, SMAD4, another substrate of USP9X, acts as a transcription factor and suppresses miR‐143 which inhibits the mRNA level of TGFBR2 by directly binding to its 3′‐untranslated region. Functionally, the maintenance of TGFBR2 by USP9X activates the TGF‐β signaling pathway, which further represses GC apoptosis. Our study highlights a functional micro‐regulatory network composed of deubiquitinase (USP9X), small noncoding RNA (miR‐143) and the TGF‐β signaling pathway, which plays a crucial role in the regulation of GC apoptosis and female fertility.

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“…Although the activity of Hippo signaling is tightly controlled through the phosphorylation cascade, it is mysterious that YAP protein is over-active, even the Hippo signaling is still functional [ 25 ]. Besides phosphorylation, several other post-translational modifications were found to play critical roles in modulation YAP protein stability and function[ 23 , 26 , 27 ]. Our previous studies revealed a few E3 ubiquitin ligases, which modulated YAP protein ubiquitination via different mechanisms [ 10 , 11 , 23 , 26 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…Besides phosphorylation, several other post-translational modifications were found to play critical roles in modulation YAP protein stability and function[ 23 , 26 , 27 ]. Our previous studies revealed a few E3 ubiquitin ligases, which modulated YAP protein ubiquitination via different mechanisms [ 10 , 11 , 23 , 26 , 28 ]. RBCK1 (RANBP2-type and C3HC4-type zinc finger-containing 1) belongs to the RING finger family and is composed of 510 amino acids [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

RBCK1 is an endogenous inhibitor for triple negative breast cancer via hippo/YAP axis

Ding

et al. 2022

Cell Commun Signal

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Background Triple negative breast cancer (TNBC) is one of the most lethal breast cancer subtypes. Due to a lack of effective therapeutic targets, chemotherapy is still the main medical treatment for TNBC patients. Thus, it is important and necessary to find new therapeutic targets for TNBC. Recent genomic studies implicated the Hippo / Yap signal is over activated in TNBC, manifesting it plays a key role in TNBC carcinogenesis and cancer progression. RBCK1 was firstly identified as an important component for linear ubiquitin assembly complex (LUBAC) and facilitates NFKB signaling in immune response. Further studies showed RBCK1 also facilitated luminal type breast cancer growth and endocrine resistance via trans-activation estrogen receptor alpha. Methods RBCK1 and YAP protein expression levels were measured by western blotting, while the mRNA levels of YAP target genes were measured by RT–PCR. RNA sequencing data were analyzed by Ingenuity Pathway Analysis. Identification of Hippo signaling activity was accomplished with luciferase assays, RT–PCR and western blotting. Protein stability assays and ubiquitin assays were used to detect YAP protein degradation. Ubiquitin-based immunoprecipitation assays were used to detect the specific ubiquitination modification on the YAP protein. Results In our current study, our data revealed an opposite function for RBCK1 in TNBC progression. RBCK1 over-expression inhibited TNBC cell progression in vitro and in vivo, while RBCK1 depletion promoted TNBC cell invasion. The whole genomic expression profiling showed that RBCK1 depletion activated Hippo/YAP axis. RBCK1 depletion increased YAP protein level and Hippo target gene expression in TNBC. The molecular biology studies confirmed that RBCK1 could bind to YAP protein and enhance the stability of YAP protein by promoting YAP K48-linked poly-ubiquitination at several YAP lysine sites (K76, K204 and K321). Conclusion Our study revealed the multi-faced RBCK1 function in different subtypes of breast cancer patients and a promising therapeutic target for TNBC treatment.

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ZNF213 negatively controls triple negative breast cancer progression via Hippo/YAP signaling

Cited by 8 publications

References 41 publications

DUB1 suppresses Hippo signaling by modulating TAZ protein expression in gastric cancer

DUB1 suppresses Hippo signaling by modulating TAZ protein expression in gastric cancer

TGFBR2 is a novel substrate and indirect transcription target of deubiquitylase USP9X in granulosa cells

RBCK1 is an endogenous inhibitor for triple negative breast cancer via hippo/YAP axis

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