Aberrant Phosphorylation of SMAD4 Thr277-Mediated USP9x–SMAD4 Interaction by Free Fatty Acids Promotes Breast Cancer Metastasis

Wu, Yong; Yu, Xiaoting; Yi, Xianghua; Wu, Ke; Dwabe, Sami; Atefi, Mohammad; Elshimali, Yahya; Kemp, Kevin T.; Bhat, Kruttika; Haro, Jesse; Sarkissyan, Marianna; Vadgama, Jaydutt V.

doi:10.1158/0008-5472.can-16-2012

Cited by 37 publications

(39 citation statements)

References 55 publications

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“…It is thus often extrapolated from these mRNA expression studies that USP9X is important to define pluripotency [4,41]. Our work clearly demonstrates that depletion of USP9X by shRNA or [36,37,49,50,70]. Our data suggest an additional function in ESC, with a new layer of regulation involving the regulation of LEFTY2 abundance, a secreted ligand that may act through cell autonomous and non-autonomous functions to regulate ESC fate.…”

Section: Usp9x Regulates the Activity Of The Pluripotency Networksupporting

confidence: 52%

USP9X deubiquitinase couples the pluripotency network and cell metabolism to regulate ESC differentiation potential

Dieuleveult

Salataj

Ransy

et al. 2020

Preprint

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Embryonic stem cells (ESC) have the unique ability to differentiate into all three germ cell layers. ESC transition through different states of pluripotency in response to growth factor signals and environmental cues before becoming terminally differentiated. Here, we demonstrated, by a multi-omic strategy, that the deubiquitinase USP9X regulates the developmental potential of ESC, and their transition from a naive to a more developmentally advance, or primed, state of pluripotency. We show that USP9X facilitates developmental gene expression and induces modifications of the mitochondrial bioenergetics, including decreased routing of pyruvate towards its oxidation and reduced respiration. In addition, USP9X binds to the pluripotency factor ESRRB, regulates its abundance and the transcriptional levels of a subset of its target genes. Finally, under permissive culture conditions, depletion of Usp9X accelerates cell differentiation in all cell lineages. We thus identified a new regulator of naive pluripotency and show that USP9X couples ESRRB pluripotency transcriptional network and cellular metabolism, both of which are important for ESC fate and pluripotency. Words: 164

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Section: Usp9x Regulates the Activity Of The Pluripotency Networksupporting

confidence: 52%

USP9X deubiquitinase couples the pluripotency network and cell metabolism to regulate ESC differentiation potential

Dieuleveult

Salataj

Ransy

et al. 2020

Preprint

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“…Moreover, depletion or inhibition of USP9X enhances the sensitivity of breast cancer cells to DNA‐damaging chemotherapeutic drugs, such as mitomycin C, cisplatin, and etoposide . In addition, USP9X contributes to obesity‐induced breast cancer metastasis . Here, we showed that shRNA‐mediated knockdown of USP9X resulted in a decrease in breast cancer cell proliferation, migration, and invasion.…”

Section: Discussionmentioning

confidence: 86%

“…21,25 In addition, USP9X contributes to obesity-induced breast cancer metastasis. 47 Here, we showed that shRNA-mediated knockdown of USP9X resulted in a decrease in breast cancer cell proliferation, migration, and invasion. However, re-expression of RNF115 in USP9X-depleted cells partially rescued cell proliferation, migration, and invasion induced by USP9X knockdown ( Figure 6).…”

Section: Discussionmentioning

confidence: 90%

“…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%

“…21 Moreover, several other studies have shown that USP9X is overexpressed in breast tumors and promotes breast tumorigenesis, progression, and chemoresistance through distinct mechanisms. 20,21,23,25,47 For example, it was shown that depletion of USP9X hinders motility of metastatic MDA-MB-231 breast cancer cells, 23 which could be an indication for the role of this protein in invasion and metastasis of breast cancer cells. Moreover, depletion or inhibition of USP9X enhances the sensitivity of breast cancer cells to DNA-damaging chemotherapeutic drugs, such as mitomycin C, cisplatin, and etoposide.…”

Section: Discussionmentioning

confidence: 99%

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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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A Novel Metabolic Reprogramming Strategy for the Treatment of Diabetes‐Associated Breast Cancer

Hao

Huang

et al. 2022

Advanced Science

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Diabetes is directly related to the risk of breast cancer (BC) occurrence and worsened BC prognosis. Currently, there are no specific treatments for diabetes‐associated BC. This paper aims to understand the fundamental mechanisms of diabetes‐induced BC progression and to develop personalized treatments. It reports a metabolic reprogramming strategy (MRS) that pharmaceutical induction of glucose import and glycolysis with metformin and NF‐κB inhibitor (NF‐κBi) while blocking the export of excessive lactate via inhibiting monocarboxylate transporter 4 (MCT4) leads to a metabolic crisis within the cancer cells. It demonstrates that the MRS shifts the metabolism of BC cells toward higher production of lactate, blocks lactate secretion, prompts intracellular acidification and induces significant cytotoxicity. Moreover, a novel MCT4 inhibitor CB‐2 has been identified by structure‐based virtual screening. A triple combination of metformin, CB‐2, and trabectedin, a drug that impedes NF‐κB signaling, strongly inhibits BC cells. Compared to normal glucose condition, MRS elicits more potent cancer cell‐killing effects under high glucose condition. Animal model studies show that diabetic conditions promote the proliferation and progression of BC xenografts in nude mice and that MRS treatment significantly inhibits HG‐induced BC progression. Therefore, inhibition of MCT4 combined with metformin/NF‐κBi is a promising cancer therapy, especially for diabetes‐associated BC.

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Aberrant Phosphorylation of SMAD4 Thr277-Mediated USP9x–SMAD4 Interaction by Free Fatty Acids Promotes Breast Cancer Metastasis

Cited by 37 publications

References 55 publications

USP9X deubiquitinase couples the pluripotency network and cell metabolism to regulate ESC differentiation potential

USP9X deubiquitinase couples the pluripotency network and cell metabolism to regulate ESC differentiation potential

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

A Novel Metabolic Reprogramming Strategy for the Treatment of Diabetes‐Associated Breast Cancer

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