Methylation silencing of ULK2 via epithelial–mesenchymal transition causes transformation to poorly differentiated gastric cancers

Motoo, Iori; Nanjo, Sohachi; Ando, Takayuki; Yamashita, Satoshi; Yasuda, Ichiro

doi:10.1007/s10120-021-01250-0

Cited by 4 publications

(3 citation statements)

References 60 publications

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“…In a pan-cancer analysis, different changes in the ULK2 transcript were observed depending on the cancer types ( 28 ). ULK2 can be silenced by methylation, which may induce epithelial-mesenchymal transition and transformation to poorly differentiated status in a gastric cancer cell line ( 29 ). Using the TCGA dataset, we found SETDB2 might be the upstream regulator of ULK2, which causes dysregulated histone methylation.…”

Section: Discussionmentioning

confidence: 99%

Analysis of exosomal competing endogenous RNA network response to paclitaxel treatment reveals key genes in advanced gastric cancer

Liu¹,

Zhang²,

Li³

et al. 2022

Front. Oncol.

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BackgroundExosome is an important component of the tumor immune microenvironment and plays critical role in cancer pathogenesis. The exosome transcriptome of gastric cancer (GC) response to paclitaxel chemotherapy has not been investigated in the past.MethodsceRNA microarrays were performed in exosomes from six advanced GC patients before and after paclitaxel treatment. Bioinformatics tools were used to identify differential expressing genes and construct competing endogenous RNA (ceRNA) networks. The importance of hub genes in the ceRNA network was confirmed by survival analysis and functional analysis.ResultsA total of 213 differential mRNAs, 370 lncRNAs, and 376 circRNAs were identified, and hub genes in ceRNA networks were screened. The differential genes were associated with GO terms SNAP complex, gap junction, protein transporter activity, cytokine receptor, and KEGG pathways synaptic vesicle cycle, propanoate metabolism, Epstein–Barr virus infection, heparin, and steroid biosynthesis, and beta-alanine metabolism. ULK2, CYP2R1, BTLA, and miR-105-5p are prognostic genes for overall survival. Paclitaxel may target ULK2 which is involved in mitosis and cell cycle. miR-105-5p may target ULK2 3’UTR.ConclusionThe work for the first time identified exosomal RNA biomarkers and constructed a ceRNA network in GC response to paclitaxel, revealed novel molecular mechanisms of GC, and provided new candidates for GC diagnosis and treatment.

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Section: Discussionmentioning

confidence: 99%

Analysis of exosomal competing endogenous RNA network response to paclitaxel treatment reveals key genes in advanced gastric cancer

Liu¹,

Zhang²,

Li³

et al. 2022

Front. Oncol.

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“…Meanwhile, autophagy activation promotes DNMT3A expression, resulting in its combination and transcriptional repression with LC3A, LC3B, and LC3BII genes (51). lncRNA MEG3 promoter methylation is also mediated by DNMT1, which in turn inhibits the ERK/p38/autophagy signaling pathway in bleomycin-induced pulmonary fibrosis (52). DNA methylation of ULK2, ATG5 gene promoter, nitro domaincontaining protein 1 (NOR1), death-associated protein kinase (DAPK), and SOX1 also impact the autophagic process (20,53,54).…”

Section: Dna Methylationmentioning

confidence: 99%

Advances in epigenetic modifications of autophagic process in pulmonary hypertension

Mao

Song

et al. 2023

Front. Immunol.

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Pulmonary hypertension is characterized by pulmonary arterial remodeling that results in increased pulmonary vascular resistance, right ventricular failure, and premature death. It is a threat to public health globally. Autophagy, as a highly conserved self-digestion process, plays crucial roles with autophagy-related (ATG) proteins in various diseases. The components of autophagy in the cytoplasm have been studied for decades and multiple studies have provided evidence of the importance of autophagic dysfunction in pulmonary hypertension. The status of autophagy plays a dynamic suppressive or promotive role in different contexts and stages of pulmonary hypertension development. Although the components of autophagy have been well studied, the molecular basis for the epigenetic regulation of autophagy is less understood and has drawn increasing attention in recent years. Epigenetic mechanisms include histone modifications, chromatin modifications, DNA methylation, RNA alternative splicing, and non-coding RNAs, which control gene activity and the development of an organism. In this review, we summarize the current research progress on epigenetic modifications in the autophagic process, which have the potential to be crucial and powerful therapeutic targets against the autophagic process in pulmonary hypertension development.

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“…Unc-51 like autophagy activating kinase 2 (ULK2), a key serine/threonine protein kinase, is pivotal in the initiation of autophagy in various cancers, including gastric cancer ( Motoo et al, 2022 ), lung adenocarcinoma ( Tsang et al, 2020 ) and prostate cancer ( Hu et al, 2020 ). Furthermore, a mounting number of studies suggest that ULK2 is implicated in cancer progression and therapy by influencing diverse cellular processes independent of its involvement in autophagy, rendering it a putative tumor suppressor gene.…”

Section: Introductionmentioning

confidence: 99%

ULK2 suppresses ovarian cancer cell migration and invasion by elevating IGFBP3

Chen,

Shao,

Liu

et al. 2024

PeerJ

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Background Ovarian cancer is an aggressive malignancy with high mortality known for its considerable metastatic potential. This study aimed to explore the expression and functional role of Unc-51 like autophagy activating kinase 2 (ULK2) in the progression of ovarian cancer. Methods ULK2 expression patterns in ovarian cancer tissues as well as benign tumor control samples obtained from our institution were evaluated using immunohistochemistry. Cell counting kit 8 and Transwell assays were applied to assess the effects of ULK2 overexpression on cell proliferation, migration and invasion, respectively. RNA sequencing was performed to explore potential mechanisms of action of ULK2 beyond its classical autophagy modulation. Results Our experiments showed significant downregulation of ULK2 in ovarian cancer tissues. Importantly, low expression of ULK2 was markedly correlated with decreased overall survival. In vitro functional studies further demonstrated that overexpression of ULK2 significantly suppressed tumor cell proliferation, migration, and invasion. RNA sequencing analysis revealed a potential regulatory role of ULK2 in the insulin signaling pathway through upregulation of insulin-like growth factor binding protein-3 (IGFBP3) in ovarian cancer cells. Conclusions In summary, the collective data indicated that ULK2 acted as a tumor suppressor in ovarian cancer by upregulating the expression of IGFBP3. Our study underscores the potential utility of ULK2 as a valuable prognostic marker for ovarian cancer.

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Methylation silencing of ULK2 via epithelial–mesenchymal transition causes transformation to poorly differentiated gastric cancers

Cited by 4 publications

References 60 publications

Analysis of exosomal competing endogenous RNA network response to paclitaxel treatment reveals key genes in advanced gastric cancer

Analysis of exosomal competing endogenous RNA network response to paclitaxel treatment reveals key genes in advanced gastric cancer

Advances in epigenetic modifications of autophagic process in pulmonary hypertension

ULK2 suppresses ovarian cancer cell migration and invasion by elevating IGFBP3

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