USP9X deubiquitinates ALDH1A3 and maintains mesenchymal identity in glioblastoma stem cells

Chen, Zhengxin; Wang, Hongwei; Wang, Shuai; Fan, Ligang; Feng, Shuang; Cai, Xiaoxiao; Peng, Chenghao; Wu, Xiaoting; Lu, Jia‐Cheng; Chen, Dan; Chen, Yuanyuan; Wu, Wenting; Lu, Daru; Liu, Ning; You, Yongping; Wang, Huibo

doi:10.1172/jci126414

Cited by 68 publications

(73 citation statements)

References 46 publications

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“…FOXD1 expression is positively associated with ALDH1A3 expression but not with expressions of other ALDH members in MES GCS . Another study showed that ALDH1A3 is deubiquitinated by the ubiquitin‐specific protease 9X (USP9X) and stabilized in MES GCS, although the USP9X preference for ALDH1A3 among many ALDH isozymes has not been addressed . Because ALDH1A3 upregulation was observed at the mRNA level in persister cells (Figure A), specific transcription factors other than FOXD1, which is overexpressed in brain but not gastric cancer (Oncomine database), may be involved in ALDH1A3 gene upregulation.…”

Section: Discussionmentioning

confidence: 99%

“…ALDH1A3 has recently been shown to play a pivotal role in mesenchymal glioma stem cell maintenance and colorectal cancer proliferation, whereas its role in gastric cancer tumorigenesis and malignancy is not clear. Here we showed that ALDH1A3 is not only a marker of persister cells after treatment with cytotoxic anticancer drugs but is also involved in the cell survival and tumor‐initiating and propagating activities of gastric cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…ALDH1A3 has recently been shown to play a pivotal role in mesenchymal glioma stem cell maintenance and colorectal cancer proliferation, 28,32 whereas its role in gastric cancer tumorigenesis and F I G U R E 6 Involvement of the mammalian target of rapamycin (mTOR) pathway in ALDH1A3-mediated drug tolerance of gastric cancer patient-derived cells. A, Gene set enrichment profiles of ALDH1A3-depleted JSC15-3 cells.…”

Section: Discussionmentioning

confidence: 99%

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ALDH1A3‐mTOR axis as a therapeutic target for anticancer drug‐tolerant persister cells in gastric cancer

et al. 2020

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Tumors consist of heterogeneous cell populations that contain cancer cell subpopulations with anticancer drug‐resistant properties called “persister” cells. While this early‐phase drug tolerance is known to be related to the stem cell‐like characteristic of persister cells, how the stem cell‐related pathways contribute to drug resistance has remained elusive. Here, we conducted a single‐cell analysis based on the stem cell lineage‐related and gastric cell lineage‐related gene expression in patient‐derived gastric cancer cell models. The analyses revealed that 5‐fluorouracil (5‐FU) induces a dynamic change in the cell heterogeneity. In particular, cells highly expressing stem cell‐related genes were enriched in the residual cancer cells after 5‐FU treatment. Subsequent functional screening identified aldehyde dehydrogenase 1A3 (ALDH1A3) as a specific marker and potential therapeutic target of persister cells. ALDH1A3 was selectively overexpressed among the ALDH isozymes after treatment with 5‐FU or SN38, a DNA topoisomerase I inhibitor. Attenuation of ALDH1A3 expression by RNA interference significantly suppressed cell proliferation, reduced the number of persister cells after anticancer drug treatment and interfered with tumor growth in a mouse xenograft model. Mechanistically, ALDH1A3 depletion affected gene expression of the mammalian target of rapamycin (mTOR) cell survival pathway, which coincided with a decrease in the activating phosphorylation of S6 kinase. Temsirolimus, an mTOR inhibitor, reduced the number of 5FU‐tolerant persister cells. High ALDH1A3 expression correlated with worse prognosis of gastric cancer patients. These observations indicate that the ALDH1A3‐mTOR axis could be a novel therapeutic target to eradicate drug‐tolerant gastric cancer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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ALDH1A3‐mTOR axis as a therapeutic target for anticancer drug‐tolerant persister cells in gastric cancer

et al. 2020

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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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“…Deubiquitinase USP9X (also known as FAM or Fat Facets in Mammals) is indispensable for embryonic development [31,32]. It plays a critical role in tissue development and homeostasis as exemplified by its implication in developmental disorders and cancers [33][34][35][36][37][38][39]. USP9X is very highly expressed in several stem cell populations compared to their differentiated counterparts, as well as in induced pluripotent cells, thus indicating USP9X expression as a marker of stemness [4,40,41].…”

Section: Introductionmentioning

confidence: 99%

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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USP9X deubiquitinates ALDH1A3 and maintains mesenchymal identity in glioblastoma stem cells

Cited by 68 publications

References 46 publications

ALDH1A3‐mTOR axis as a therapeutic target for anticancer drug‐tolerant persister cells in gastric cancer

ALDH1A3‐mTOR axis as a therapeutic target for anticancer drug‐tolerant persister cells in gastric cancer

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

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

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