SPOP Promotes Nanog Destruction to Suppress Stem Cell Traits and Prostate Cancer Progression

Zhang, Jinfang; Chen, Ming; Zhu, Yasheng; Dai, Xiangpeng; Dang, Fabin; Ren, Junming; Ren, Shancheng; Shulga, Yulia V.; Beça, Francisco; Gan, Wenjian; Wu, Fei; Lin, Yu‐Min; Zhou, Xiaobo; DeCaprio, James A.; Beck, Andrew H.; Lu, Kun Ping; Huang, Jiaoti; Zhao, Cheryl; Sun, Yinghao; Gao, Xu; Pandolfi, Pier Paolo; Wei, Wenyi

doi:10.1016/j.devcel.2018.11.035

Cited by 57 publications

(52 citation statements)

References 68 publications

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“…4a). 282,283 As ubiquitination is a reversible process, Nanog may also be regulated by deubiquitinating enzymes during stem cell or somatic cell reprogramming. To screen the DUB of Nanog, the deubiquitinating enzyme USP21 was identified by the efficient dual-luciferase reporter assay system.…”

Section: Nanog Ubiquitinationmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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Section: Nanog Ubiquitinationmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

Self Cite

470

308

View full text Add to dashboard Cite

show abstract

“…Importantly, KPT-6566 treatments caused selective killing of malignant cells and also suppressed the CSC-like phenotype in vitro and metastasis growth in the lungs [201]. Another small molecule inhibitor of PIN1, PiB, inhibited both SPOP-mediated NANOG degradation and stemness-associated spheroid formation in prostate cancer cells [197]; the application of PIN1 inhibitors against prostate cancer with wild-type SPOP was suggested by the researchers. As for pharmaceutical targeting, all-trans retinoic acid-mediated inhibition of PIN1 was shown to eliminate gastric CSCs and also impair their self-renewal and tumorigenic potential [189].…”

Section: Targeting Peptidyl-prolyl Isomerases and Use Of Fkbpl-derivementioning

confidence: 99%

“…In fact, PIN1 overexpression may be an essential cause for the tumorigenesis and cancer stemness development in breast and pancreatic carcinomas [186,195,196]. Studies of the roles of SPOP and PIN1 in prostate cancer stemness and progression have revealed that PIN1 is an upstream regulator of NANOG and also protects the latter from SPOP-mediated polyubiquitination and degradation, thus promoting NANOG-conferred cancer stemness features in prostate tumors [197].…”

Section: Immunophilins and Immunophilin-like Peptidyl-prolyl Isomerasesmentioning

confidence: 99%

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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“…As an adaptor of Cul3-based ubiquitin ligase, SPOP is ubiquitously expressed, although in varied quantities, in different tissues [31]. It affects many biological processes by binding and triggering the ubiquitination and proteasomal degradation of target proteins [21,32]. Previous research indicates that SPOP binds with MyD88 and promotes the degradation [23].…”

Section: Discussionmentioning

confidence: 99%

Association of SPOP Expression with the Immune Response to Salmonella Infection in Chickens

Wang

et al. 2020

Animals

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Salmonellosis is a zoonosis that is not only harmful to the health of poultry but also poses a threat to human health. Although many measures have been put in place to reduce morbidity, they have not provided satisfactory results. Therefore, it is necessary to clarify the immune mechanisms involved in improving the resistance of chickens against Salmonella. BTB (Broad-complex Tramtrack and Bric-a-brac) Speckle-type POZ (poxvirus and zinc finger) protein (SPOP) regulates protein expression by promoting substrate ubiquitination and degradation. The correlation between SPOP expression and the immune response has not been fully described. Therefore, the aim of this study was to clarify this relationship. In vitro, we stimulated chicken macrophage cells (HD11) with lipopolysaccharide, then analyzed the correlation between SPOP and IL1β or IL8 expression using quantitative real-time polymerase chain reaction (qRT-PCR). In vivo, we infected 7-days-old chickens with Salmonella Typhimurium, then analyzed the association between SPOP expression and the immune response, including IL1β and IL8 expression, IgA production, and bacterial loads. We found that SPOP may participate in the regulation of the immune response in macrophage cells. SPOP expression was negatively correlated with IL-1β and IL-8 expression both in vivo and in vitro. SPOP expression was also negatively related to bacterial loads and immunoglobulin (Ig) A production. These results indicate that SPOP may have important functions in the response to Salmonella infection.

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SPOP Promotes Nanog Destruction to Suppress Stem Cell Traits and Prostate Cancer Progression

Cited by 57 publications

References 68 publications

The role of ubiquitination in tumorigenesis and targeted drug discovery

The role of ubiquitination in tumorigenesis and targeted drug discovery

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Association of SPOP Expression with the Immune Response to Salmonella Infection in Chickens

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