USP9X regulates centrosome duplication and promotes breast carcinogenesis

Li, Xin; Song, Nan; Liu, Ling; Liu, Xinhua; Ding, Xiang; Song, Xin; Yang, Shangda; Lin, Shuo; Zhou, Xing; Su, Dongxue; Wang, Yue; Zhang, Qi; Cao, Cheng; Ma, Shuai; Yu, Na; Yang, Fuquan; Wang, Yan; Yao, Zhi; Shang, Yongfeng; Shi, Lei

doi:10.1038/ncomms14866

Cited by 98 publications

(131 citation statements)

References 67 publications

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“…This study has uncovered core molecular machinery that controls centrosome anchoring, mitotic spindle geometry, genome segregation, and multicellular assembly. Perturbation of these processes by diverse oncogenic pressures may provide a phylogenetic basis for branched evolution of genomic and morphological phenotypes underlying cancer trajectories to more aggressive subtypes.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C zeta suppresses low‐ or high‐grade colorectal cancer (CRC) phenotypes by interphase centrosome anchoring

Deevi

Javadi

McClements

et al. 2018

The Journal of Pathology

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Histological grading provides prognostic stratification of colorectal cancer (CRC) by scoring heterogeneous phenotypes. Features of aggressiveness include aberrant mitotic spindle configurations, chromosomal breakage, and bizarre multicellular morphology, but pathobiology is poorly understood. Protein kinase C zeta (PKCz) controls mitotic spindle dynamics, chromosome segregation, and multicellular patterns, but its role in CRC phenotype evolution remains unclear. Here, we show that PKCz couples genome segregation to multicellular morphology through control of interphase centrosome anchoring. PKCz regulates interdependent processes that control centrosome positioning. Among these, interaction between the cytoskeletal linker protein ezrin and its binding partner NHERF1 promotes the formation of a localized cue for anchoring interphase centrosomes to the cell cortex. Perturbation of these phenomena induced different outcomes in cells with single or extra centrosomes. Defective anchoring of a single centrosome promoted bipolar spindle misorientation, multi‐lumen formation, and aberrant epithelial stratification. Collectively, these disturbances induce cribriform multicellular morphology that is typical of some categories of low‐grade CRC. By contrast, defective anchoring of extra centrosomes promoted multipolar spindle formation, chromosomal instability (CIN), disruption of glandular morphology, and cell outgrowth across the extracellular matrix interface characteristic of aggressive, high‐grade CRC. Because PKCz enhances apical NHERF1 intensity in 3D epithelial cultures, we used an immunohistochemical (IHC) assay of apical NHERF1 intensity as an indirect readout of PKCz activity in translational studies. We show that apical NHERF1 IHC intensity is inversely associated with multipolar spindle frequency and high‐grade morphology in formalin‐fixed human CRC samples. To conclude, defective PKCz control of interphase centrosome anchoring may underlie distinct categories of mitotic slippage that shape the development of low‐ or high‐grade CRC phenotypes. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

Protein kinase C zeta suppresses low‐ or high‐grade colorectal cancer (CRC) phenotypes by interphase centrosome anchoring

Deevi

Javadi

McClements

et al. 2018

The Journal of Pathology

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“…As both USP9X and RNF115 have been reported to promote breast cancer cell proliferation, migration, and invasion, we next determined whether the biological function of USP9X in breast cancer cells depends on RNF115. USP9X‐depleted MCF‐7 and MDA‐MB‐231 cells were infected with lentiviral expression vector encoding either pLVX empty vector or pLVX‐Flag‐RNF115.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, another study reported that USP9X deubiquitinates and stabilizes YAP1, a major downstream effector of the Hippo pathway, thus promoting breast cancer cell survival and chemoresistance . Moreover, several other studies have shown that USP9X is overexpressed in breast tumors and promotes breast tumorigenesis, progression, and chemoresistance through distinct mechanisms . For example, it was shown that depletion of USP9X hinders motility of metastatic MDA‐MB‐231 breast cancer cells, which could be an indication for the role of this protein in invasion and metastasis of breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinase ubiquitin‐specific protease 9X regulates the stability and function of E3 ubiquitin ligase ring finger protein 115 in breast cancer cells

Shao

et al. 2019

Cancer Science

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The E3 ubiquitin ligase ring finger protein 115 ( RNF 115) is overexpressed in more than half of human breast tumors and is implicated in the pathogenesis and progression of breast cancer. However, the mechanism behind RNF 115 overexpression in breast tumors remains largely unknown. Here we report that ubiquitin‐specific protease 9X ( USP 9X), a substrate‐specific deubiquitinating enzyme, stabilizes RNF 115 and thereby regulates its biological functions in breast cancer cells. Immunoprecipitation and GST pull‐down assays showed that USP 9X interacted with RNF 115. Depletion of RNF 115 by si RNA s or overexpression of RNF 115 did not significantly affect USP 9X expression. In contrast, knockdown of USP 9X in breast cancer cells by si RNA s reduced RNF 115 protein abundance, which was partially restored following treatment with proteasome inhibitor MG ‐132. Moreover, depletion of USP 9X reduced the half‐life of RNF 115 and increased its ubiquitination. Conversely, overexpression of USP 9X resulted in an accumulation of RNF 115 protein, accompanied by a decrease in its ubiquitination. RNF 115 mRNA levels were unaffected by overexpression or knockdown of USP 9X. Furthermore, USP 9X protein expression levels correlated positively with RNF 115 in breast cancer cell lines and breast tumor samples. Importantly, reintroduction of RNF 115 in USP 9X‐depleted cells partially rescued the reduced proliferation, migration, and invasion of breast cancer cells by USP 9X knockdown. Collectively, these findings indicate that USP 9X is a stabilizer of RNF 115 protein and that the USP 9X‐ RNF 115 signaling axis is implicated in the breast cancer malignant phenotype.

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“…Furthermore, multiple myeloma patients with high level of USP9X had a poorer overall survival rate and prognosis compared to patient with lower USP9X levels (Schwickart et al, 2010). USP9X can also regulate and stabilize CEP131, a centriolar satellite protein, ultimately promoting breast carcinogenesis, indicating that USP9X is a significant regulator of centrosome biogenesis and revealing a critical role for the USP9X/CEP131 axis in breast carcinogenesis (Li et al, 2017). In addition, USP9X can also function as a tumor suppressor.…”

Section: The Roles Of Usps In Cancermentioning

confidence: 99%

Inhibition of Ubiquitin-Specific Proteases as a Novel Anticancer Therapeutic Strategy

et al. 2018

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Dysfunction or dysregulation of the ubiquitin proteasome system (UPS) is closely related to tumorigenesis and the development of multiple cancers. Targeting the UPS provides a new anticancer therapeutic strategy, but clinically available UPS-targeted inhibitors, including lenalidomide and bortezomib, are limited to treat solid tumors. Under physiological conditions, deubiquitinases or deubiquitinating enzymes (DUBs) play vital roles in the UPS by removing ubiquitin from substrate proteins and regulating their proteasomal degradation and sub-localization, thus maintaining the balance between ubiquitination and deubiquitination for protein quality control and homeostasis. The aberrant expression or function of DUBs generally leads to the occurrence and progression of a series of disorders, including malignant tumors. Therefore, targeting DUBs is a novel anticancer therapeutic strategy. Ubiquitin-specific proteases (USPs) are the largest subfamily of DUBs which have attracted considerable interest as anticancer targets. Most of USPs are abnormally activated or expressed in a variety of malignant tumors or in the tumor microenvironment, making them ideal anticancer target candidates, which indicates that USPs inhibitors may be a class of potential anticancer therapeutic agents. However, there are no relevant inhibitors targeting USPs have entered clinical trial so far. In this review, we will summarize the roles and mechanisms of USPs in malignant transformation and progression as well as recent advances of small-molecule inhibitors targeting USPs.

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USP9X regulates centrosome duplication and promotes breast carcinogenesis

Cited by 98 publications

References 67 publications

Protein kinase C zeta suppresses low‐ or high‐grade colorectal cancer (CRC) phenotypes by interphase centrosome anchoring

Protein kinase C zeta suppresses low‐ or high‐grade colorectal cancer (CRC) phenotypes by interphase centrosome anchoring

Deubiquitinase ubiquitin‐specific protease 9X regulates the stability and function of E3 ubiquitin ligase ring finger protein 115 in breast cancer cells

Inhibition of Ubiquitin-Specific Proteases as a Novel Anticancer Therapeutic Strategy

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