The deubiquitinase USP9X regulates FBW7 stability and suppresses colorectal cancer

Khan, Omar M.; Carvalho, Joana; Spencer‐Dene, Bradley; Mitter, Richard; Frith, David; Snijders, Ambrosius P.; Wood, Stephen A.; Behrens, Axel

doi:10.1172/jci97325

Cited by 92 publications

(64 citation statements)

References 43 publications

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“…In addition, USP9X and USP13 have been reported to deubiquitinate MCL1 for stabilization (10,11). However, USP9X exhibits tissue-specific expression primarily in the brain and immune system (12), and sometimes functions as a tumor suppressor in certain biological processes and malignancies (13,14). Similarly, USP13 acts as a tumor suppressor by stabilizing PTEN expression in breast cancer (15).…”

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confidence: 99%

MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer

Luo

Zhao

et al. 2019

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

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Chemoresistance is a severe outcome among patients with ovarian cancer that leads to a poor prognosis. MCL1 is an antiapoptotic member of the BCL-2 family that has been found to play an essential role in advancing chemoresistance and could be a promising target for the treatment of ovarian cancer. Here, we found that deubiquitinating enzyme 3 (DUB3) interacts with and deubiquitinates MCL1 in the cytoplasm of ovarian cancer cells, which protects MCL1 from degradation. Furthermore, we identified that O6-methylguanine-DNA methyltransferase (MGMT) is a key activator of DUB3 transcription, and that the MGMT inhibitor PaTrin-2 effectively suppresses ovarian cancer cells with elevated MGMT-DUB3-MCL1 expression both in vitro and in vivo. Most interestingly, we found that histone deacetylase inhibitors (HDACis) could significantly activate MGMT/DUB3 expression; the combined administration of HDACis and PaTrin-2 led to the ideal therapeutic effect. Altogether, our results revealed the essential role of the MGMT-DUB3-MCL1 axis in the chemoresistance of ovarian cancer and identified that a combined treatment with HDACis and PaTrin-2 is an effective method for overcoming chemoresistance in ovarian cancer.

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confidence: 99%

MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer

Luo

Zhao

et al. 2019

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

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“…26,36,[38][39][40][41][42][43] Conversely, USP9X has tumor suppressor functions in pancreatic ductal adenocarcinoma 37,44,45 and colorectal cancer. 46 Interestingly, 2 recent studies showed that USP9X stabilizes large tumor suppressor kinase 2, an upstream component of the Hippo pathway, to negatively regulate YAP and its target genes to suppress tumor growth in pancreatic 44,45 and breast 44 cancer. 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.…”

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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“…The function of USP9x is cell-type specific. USP9x has been viewed as a tumor suppressor gene in colorectal and pancreatic ductal adenocarcinoma, while others reported that USP9x is an oncogene in breast cancer, glioblastoma, and leukemia (Akiyama et al, 2019;Chen et al, 2019;Khan et al, 2018a;Pal et al, 2018;Potu et al, 2017b;Zhu et al, 2018). Our results suggest that USP9x may function as an oncoprotein through regulating SOX2 in osteosarcoma.…”

Section: Many Transcription Factors Have Been Involved In the Pathogementioning

confidence: 99%

Targeting USP9x/SOX2 axis contributes to the anti-osteosarcoma effect of neogambogic acid

Chen

Zhang

Cai

et al. 2019

Preprint

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SOX2 has been viewed as a critical oncoprotein in osteosarcoma. Emerging evidence show that inducing the degradation of transcription factors such as SOX2 is a promising strategy to make them druggable. Here, we show that neogambogic acid (NGA), an active ingredients in garcinia, significantly inhibited the proliferation of osteosarcoma cells with ubiquitin proteasome-mediated degradation of SOX2 in vitro and in vivo. We further identified USP9x as a bona fide deubiquitinase for SOX2 and NGA directly interacts with USP9x in cells. Moreover, knockdown of USP9x inhibited the proliferation and colony formation of osteosarcoma cells, which could be rescued by overexpression of SOX2. Consistent with this, knockdown of USP9x inhibited the proliferation of osteosarcoma cells in a xenograft mouse model.Collectively, we identify USP9x as the first deubiquitinating enzyme for controlling the stability of SOX2 and USP9x is a direct target for NGA. We propose that targeting the USP9x/SOX2 axis represents a novel strategy for the therapeutic of osteosarcoma and other SOX2 related cancers.

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The deubiquitinase USP9X regulates FBW7 stability and suppresses colorectal cancer

Cited by 92 publications

References 43 publications

MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer

MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer

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

Targeting USP9x/SOX2 axis contributes to the anti-osteosarcoma effect of neogambogic acid

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