Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway

Zhu, Chengzhan; Ji, Xinyan; Zhang, Haitao; Zhou, Qi; Cao, Xiaolei; Tang, Mei; Su, Yuan; Yan, Huan; Li, Li; Liang, Tingbo; Feng, Xin‐Hua; Zhao, Bin

doi:10.1074/jbc.ra117.000392

Cited by 49 publications

(30 citation statements)

References 66 publications

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“…Previously, USP9X has been shown to regulate Hippo signaling pathway as a broad DUB for angiomotin, Kibra, WW45, and LATS2 (48)(49)(50). Under physiologic conditions, BAP1 is mainly localized in the nucleus (37).…”

Section: Discussionmentioning

confidence: 99%

The Tumor Suppressor BAP1 Regulates the Hippo Pathway in Pancreatic Ductal Adenocarcinoma

Lee¹,

Pham²,

Chang³

et al. 2020

Cancer Research

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The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with a high risk for mesothelioma and melanocytic tumors. Here, we show that pancreatic intraepithelial neoplasia driven by oncogenic mutant KrasG12D progressed to pancreatic adenocarcinoma in the absence of BAP1. The Hippo pathway was deregulated in BAP1-deficient pancreatic tumors, with the tumor suppressor LATS exhibiting enhanced ubiquitin-dependent proteasomal degradation. Therefore, BAP1 may limit tumor progression by stabilizing LATS and thereby promoting activity of the Hippo tumor suppressor pathway. Significance: BAP1 is mutated in a broad spectrum of tumors. Pancreatic Bap1 deficiency causes acinar atrophy but combines with oncogenic Ras to produce pancreatic tumors. BAP1-deficient tumors exhibit deregulation of the Hippo pathway. See related commentary by Brekken, p. 1624

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Section: Discussionmentioning

confidence: 99%

The Tumor Suppressor BAP1 Regulates the Hippo Pathway in Pancreatic Ductal Adenocarcinoma

Lee¹,

Pham²,

Chang³

et al. 2020

Cancer Research

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“…Hippo pathway is a conserved pathway that controls cell proliferation, organ size, tissue regeneration, and stem cell self-renewal by regulating the downstream transcriptional coactivators YAP and TAZ [9][10][11] . Among the core kinase components of the Hippo pathway, the Dbf2-related kinases LATS1 and LATS2 (LATS1/2) have gained increasing attention.…”

Section: Introductionmentioning

confidence: 99%

circRNA_0000140 suppresses oral squamous cell carcinoma growth and metastasis by targeting miR-31 to inhibit Hippo signaling pathway

et al. 2020

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Oral squamous cell carcinoma (OSCC) is one of the most common malignancies and has a poor prognosis. Circular RNA (circRNA) has been increasingly recognized as a crucial contributor to carcinogenesis. circRNA_0000140 has been aberrantly expressed in OSCC, but its role in tumor growth and metastasis remains largely unclear. Sanger sequencing, actinomycin D, and RNase R treatments were used to confirm head-to-tail junction sequences and the stability of circ_0000140. In vitro cell activities, including proliferation, migration, invasion, and apoptosis, were determined by colony formation, transwell, and flow cytometry assays. The expression levels of circ_0000140, Hippo signaling pathway, and serial epithelial-mesenchymal transition (EMT) markers were measured by quantitative real-time PCR, western blotting, immunofluorescence, and immunohistochemistry. Dual luciferase reporter assays and Argonaute 2-RNA immunoprecipitation assays were performed to explore the interplay among circ_0000140, miR-31, and LATS2. Subcutaneous tumor growth was observed in nude mice, in which in vivo metastasis was observed following tail vein injection of OSCC cells. circ_0000140 is derived from exons 7 to 10 of the KIAA0907 gene. It was down-regulated in OSCC tissues and cell lines, and correlated negatively with poor prognostic outcomes in OSCC patients. Gain-offunction experiments demonstrated that circ_0000140 enhancement suppressed cell proliferation, migration, and invasion, and facilitated cell apoptosis in vitro. In xenograft mouse models, overexpression of circ_0000140 was able to repress tumor growth and lung metastasis. Furthermore, mechanistic studies showed that circ_0000140 could bind with miR-31 and up-regulate its target gene LATS2, thus affecting OSCC cellular EMT. Our findings demonstrated the roles of circ_0000140 in OSCC tumorigenesis as well as in metastasis, and circ_0000140 exerts its tumor-suppressing effect through miR-31/LATS2 axis of Hippo signaling pathway in OSCC.

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“…35 In Hippo/YAP signaling, LATS2 is activated by MST1/2-induced phosphorylation and then phosphorylates and inhibits YAP-mediated gene transcription; most of YAP target genes positively regulates cell cycle and stemness maintenance. 36,37 In this study, we found that LATS2, the potential target of miR-520b ( Figure 4A), was downregulated by miR-520b overexpression ( Figure 4B). Correspondingly, the target genes of Hippo/YAP signaling pathway were inhibited in miR-520b-overexpressing cells ( Figure 4C).…”

Section: Discussionmentioning

confidence: 52%

<p>miR-520b Promotes Breast Cancer Stemness Through Hippo/YAP Signaling Pathway</p>

Zhang

Lang

Zou

et al. 2019

OTT

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The breast cancer stem cells contribute to the initiation, progression, recurrence, metastasis as well as resistance of breast cancer. However, the mechanisms underlying the maintenance of breast cancer stemness have not been fully understood. Materials and methods: TCGA and GEO data were used for measuring miR-520b expression in breast cancer tissues. Kaplan-meier analysis was used for determining the relationship between miR-520b expression level and the prognosis of patients. Genetic manipulation was performed by lentivirus system and miR-520b inhibitor was used for knockdown of miR-520b. qRT-PCR and Western blot were employed to determine the mRNA and protein levels, respectively. The stemness and EMT (Epithelial to mesenchymal transition) were assessed by sphereformation and transwell assay as well as the expression of the related markers. The target genes of miR-520b were identified using the online database starBase V3.0. Results: miR-520b is upregulated in cancer tissues of breast cancer patients and predicts poor prognosis. Upregulation of miR-520b was found in breast cancer stem cells. Ectopic expression of miR-520b promotes the stemness of the breast cancer cells, conversely, depletion of miR-520b attenuates the stemness of these cells. miR-520b positively regulates Hippo/YAP signaling pathway and overexpression of LAST2 abolished the effect of miR-520b on the stemness of breast cancer cells. Conclusion: miR-520b promotes the stemness of breast cancer patients by activating Hippo/YAP signaling via targeting LATS2.

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Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway

Cited by 49 publications

References 66 publications

The Tumor Suppressor BAP1 Regulates the Hippo Pathway in Pancreatic Ductal Adenocarcinoma

The Tumor Suppressor BAP1 Regulates the Hippo Pathway in Pancreatic Ductal Adenocarcinoma

circRNA_0000140 suppresses oral squamous cell carcinoma growth and metastasis by targeting miR-31 to inhibit Hippo signaling pathway

<p>miR-520b Promotes Breast Cancer Stemness Through Hippo/YAP Signaling Pathway</p>

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