Lysine demethylase 2 (KDM2B) regulates hippo pathway via MOB1 to promote pancreatic ductal adenocarcinoma (PDAC) progression

Quan, Ming; Chen, Zhi Qin; Jiao, Feng; Xiao, Xiuying; Xia, Qing; Chen, Jingde; Qian, Chao; Li, Yandong; Yang, Haiyan; Cui, Jiujie

doi:10.1186/s13046-019-1489-0

Cited by 19 publications

(19 citation statements)

References 49 publications

(80 reference statements)

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“…In accordance to our results, the mRNA expression of MOB3B is significantly lower in PCa tissues than in healthy control tissues, which is further closely associated with aggressive pathophysiological features in patients with PCa [21]. By directly binding to the promoter region of MOB1, KDM2B has been demonstrated to suppress the promoter activity of MOB1 and transcriptionally inhibit MOB1 expression, thus augmenting the proliferation, migration and invasion of pancreatic ductal adenocarcinoma cells [22], which is partially in consistent with our results. Furthermore, in the response of both PC3 cell line and nude mice to KDM5A overexpression, the mRNA and protein levels of YTHDF2 was found to be significantly downregulated.…”

Section: Discussionsupporting

confidence: 92%

Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression

Feng

et al. 2020

J Exp Clin Cancer Res

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Background Accumulating evidence supports that lysine-specific demethylase 5 (KDM5) family members act as oncogenic drivers. This study was performed to elucidate the potential effects of KDM5A on prostate cancer (PCa) progression via the miR-495/YTHDF2/m6A-MOB3B axis. Methods The expression of KDM5A, miR-495, YTHDF2 and MOB3B was validated in human PCa tissues and cell lines. Ectopic expression and knockdown experiments were developed in PCa cells to evaluate their effects on PCa cell proliferation, migration, invasion and apoptosis. Mechanistic insights into the interaction among KDM5A, miR-495, YTHDF2 and MOB3B were obtained after dual luciferase reporter, ChIP, and PAR-CLIP assays. Me-RIP assay was used to determine m6A modification level of MOB3B mRNA in PCa cells. Mouse xenograft models of PCa cells were also established to monitor the tumor growth. Results KDM5A was highly expressed in human PCa tissues and cell lines. Upregulated KDM5A stimulated PCa cell proliferation, migration and invasion, but reduced cell apoptosis. Mechanistically, KDM5A, as a H3K4me3 demethylase, bound to the miR-495 promoter, which led to inhibition of its transcription and expression. As a target of miR-495, YTHDF2 could inhibit MOB3B expression by recognizing m6A modification of MOB3B mRNA and inducing mRNA degradation. Furthermore, KDM5A was found to downregulate MOB3B expression, consequently augmenting PCa cell proliferation, migration and invasion in vitro and promoting tumor growth in vivo via the miR-495/YTHDF2 axis. Conclusion In summary, our study highlights the potential of histone demethylase KDM5A activity in enhancing PCa progression, and suggests KDM5A as a promising target for PCa treatment.

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Section: Discussionsupporting

confidence: 92%

Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression

Feng

et al. 2020

J Exp Clin Cancer Res

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“…36 In another study of pancreatic ductal adenocarcinoma, lysine demethylase 2 (KDM2B) suppressed the expression of MOB1 by its binding to the promoter region of MOB1, then YAP-mediated transcription promoted the invasion, migration and proliferation of cancer cells. 37 Contrary to these reports, in our study MOB1 increased the migration ability of cancer cells. Our microarray results suggest that MOB1 in NSCLC could predominantly regulate the expression of genes promoting cancer invasiveness such as MCAM and ADAM12.…”

Section: Discussioncontrasting

confidence: 99%

“…In hepatocellular carcinoma, MOB2 negatively regulates phosphorylation of MOB1 and LATS which could lead to YAP activation and increased motility of cancer cells 36 . In another study of pancreatic ductal adenocarcinoma, lysine demethylase 2 (KDM2B) suppressed the expression of MOB1 by its binding to the promoter region of MOB1, then YAP‐mediated transcription promoted the invasion, migration and proliferation of cancer cells 37 . Contrary to these reports, in our study MOB1 increased the migration ability of cancer cells.…”

Section: Discussioncontrasting

confidence: 91%

Association of Mps one binder kinase activator 1 (MOB1) expression with poor disease‐free survival in individuals with non‐small cell lung cancer

et al. 2020

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Background: Mps one binder kinase activator 1 (MOB1) is a core component of the Hippo signaling pathway and has been implicated as a tumor suppressor. Here, we evaluated the possible relationship of MOB1 expression in non-small cell lung cancer (NSCLC) to prognosis. Methods: We retrospectively analyzed 205 lung adenocarcinoma patients treated at Kyushu University Hospital between November 2007 and October 2012. MOB1 expression in tumor cells of surgical specimens was evaluated by immunohistochemistry. Invasive activity of NSCLC cell lines in vitro was measured with a transwell assay. Results: Expression of MOB1 was classified as high in 105 of the 205 (51.2%) tumor specimens, and such high expression was significantly associated with poor disease-free survival (P = 0.0161). Among the various clinicopathologic parameters examined, high MOB1 expression was significantly associated only with intratumoral vascular invasion (P = 0.0005). Multivariate analysis also identified high MOB1 expression as a significant independent risk factor for diseasefree survival (P = 0.0319). The invasiveness of H1299 cells in vitro was increased or attenuated by overexpression or knockdown of MOB1, respectively. Conclusions: Our results suggest that MOB1 might promote early recurrence of NSCLC by increasing vascular invasion by tumor cells.

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“…Data on transcriptional regulation of Mob genes is scarce, but alteration of DNA methylation patterns has been proposed as a possible mechanism to affect regulation of the levels of MOB proteins and is often associated to cancer. Studies of DNA methylation patterns revealed that lysine demethylase 2B (KDM2B) directly bound to the promoter region of HsMob1 gene, inhibited and promoted pancreatic ductal adenocarcinoma progression [84]. Furthermore, in a study concerning methylation in human breast cancer in response to resveratrol, HsMOB1 promotor presented methylation changes in triple-negative breast cancer cells [85].…”

Section: Transcriptional and Post-transcriptional Regulation Of Mobsmentioning

confidence: 99%

MOB: Pivotal Conserved Proteins in Cytokinesis, Cell Architecture and Tissue Homeostasis

Delgado

Carmona

Nolasco

et al. 2020

Biology

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The MOB family proteins are constituted by highly conserved eukaryote kinase signal adaptors that are often essential both for cell and organism survival. Historically, MOB family proteins have been described as kinase activators participating in Hippo and Mitotic Exit Network/ Septation Initiation Network (MEN/SIN) signaling pathways that have central roles in regulating cytokinesis, cell polarity, cell proliferation and cell fate to control organ growth and regeneration. In metazoans, MOB proteins act as central signal adaptors of the core kinase module MST1/2, LATS1/2, and NDR1/2 kinases that phosphorylate the YAP/TAZ transcriptional co-activators, effectors of the Hippo signaling pathway. More recently, MOBs have been shown to also have non-kinase partners and to be involved in cilia biology, indicating that its activity and regulation is more diverse than expected. In this review, we explore the possible ancestral role of MEN/SIN pathways on the built-in nature of a more complex and functionally expanded Hippo pathway, by focusing on the most conserved components of these pathways, the MOB proteins. We discuss the current knowledge of MOBs-regulated signaling, with emphasis on its evolutionary history and role in morphogenesis, cytokinesis, and cell polarity from unicellular to multicellular organisms.

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Lysine demethylase 2 (KDM2B) regulates hippo pathway via MOB1 to promote pancreatic ductal adenocarcinoma (PDAC) progression

Cited by 19 publications

References 49 publications

Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression

Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression

Association of Mps one binder kinase activator 1 (MOB1) expression with poor disease‐free survival in individuals with non‐small cell lung cancer

MOB: Pivotal Conserved Proteins in Cytokinesis, Cell Architecture and Tissue Homeostasis

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