Long noncoding RNA LINC00261 induces chemosensitization to 5‐fluorouracil by mediating methylation‐dependent repression of DPYD in human esophageal cancer

Lin, Kai Hsin; Jiang, Hong; Zhuang, Shan-Shan; Qin, Yun-Sheng; Qiu, Guodong; She, Yuqi; Zheng, Jieting; Chen, Chen; Fang, Ling; Zhang, Shu-Yao

doi:10.1096/fj.201800759r

Cited by 47 publications

(36 citation statements)

References 32 publications

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“…Importantly, while the study of Chen and colleagues largely complements and supports major findings of our study, we did not identify FOXO3, β-catenin, or TCF4 as commonly deregulated genes, and TCF4 expression was only significantly upregulated (log2FC = 1.76) in LINC00261 promoter knockout clones rather than wild-type clones. Moreover, our own cell fractionation analysis in a panel of lung and pancreas cell lines revealed a predominant nuclear localization of LINC00261, which is supported by other studies in mouse hepatocytes [43], esophageal cancer cells [76], and lung epithelial cells [44]. This localization pattern might suggest a role for LINC00261 in the control of target gene transcription, e.g., through the recruitment of undefined transcription factors or by the regulation of higher order chromatin folding.…”

Section: Discussionsupporting

confidence: 87%

LINC00261 Is Differentially Expressed in Pancreatic Cancer Subtypes and Regulates a Pro-Epithelial Cell Identity

Dorn

Glaß

Neu

et al. 2020

Cancers

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Pancreatic adenocarcinoma (PDAC) is one of the major causes of cancer-associated deaths worldwide, with a dismal prognosis that has not significantly changed over the last decades. Transcriptional analysis has provided valuable insights into pancreatic tumorigenesis. Specifically, pancreatic cancer subtypes were identified, characterized by specific mutations and gene expression changes associated with differences in patient survival. In addition to differentially regulated mRNAs, non-coding RNAs, including long non-coding RNAs (lncRNAs), were shown to have subtype-specific expression patterns. Hence, we aimed to characterize prognostic lncRNAs with deregulated expression in the squamous subtype of PDAC, which has the worst prognosis. Extensive in silico analyses followed by in vitro experiments identified long intergenic non-coding RNA 261 (LINC00261) as a downregulated lncRNA in the squamous subtype of PDAC, which is generally associated with transforming growth factor β (TGFβ) signaling in human cancer cells. Its genomic neighbor, the transcription factor forkhead box protein A2 (FOXA2), regulated LINC00261 expression by direct binding of the LINC00261 promoter. CRISPR-mediated knockdown and promoter knockout validated the importance of LINC00261 in TGFβ-mediated epithelial–mesenchymal transition (EMT) and established the epithelial marker E-cadherin, an important cell adhesion protein, as a downstream target of LINC00261. Consequently, depletion of LINC00261 enhanced motility and invasiveness of PANC-1 cells in vitro. Altogether, our data suggest that LINC00261 is an important tumor-suppressive lncRNA in PDAC that is involved in maintaining a pro-epithelial state associated with favorable disease outcome.

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Section: Discussionsupporting

confidence: 87%

LINC00261 Is Differentially Expressed in Pancreatic Cancer Subtypes and Regulates a Pro-Epithelial Cell Identity

Dorn

Glaß

Neu

et al. 2020

Cancers

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“…Recent studies have shown that lncRNA dysregulation is involved in various malignancies, such as lung cancer 4 , esophageal cancer 5 , gastric cancer 6 , liver cancer 7 and PC 8 , 9 , by affecting diverse tumor biological behaviors, such as proliferation, invasion, migration and metastasis, both in vitro and in vivo. Increasing numbers of lncRNA studies in PC have been reported 9 - 12 .…”

Section: Introductionmentioning

confidence: 99%

Methylation-mediated LINC00261 suppresses pancreatic cancer progression by epigenetically inhibiting c-Myc transcription

Liu¹,

Zheng²,

Zhang³

et al. 2020

Theranostics

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Background: Due to the limitations of strategies for its early diagnosis and treatment, pancreatic cancer (PC) remains a substantial human health threat. We previously discovered a methylation-mediated lncRNA, LINC00261, which is downregulated in PC tissues. However, the underlying role of LINC00261 in PC remains largely unknown. Methods: Quantitative real-time PCR and in situ hybridization were performed to evaluate the expression levels of LINC00261 in PC, adjacent nontumor and normal pancreas tissues. The clinical significance of LINC00261 was assessed in multicenter PC samples. The functions of LINC00261 in PC were investigated by gain- and loss-of-function assays in vitro and in vivo . Potential downstream pathways and mechanisms were explored via RNA sequencing and bioinformatic analyses. RNA immunoprecipitation and chromatin immunoprecipitation assays were used to validate the underlying mechanisms. Pyrosequencing and targeted demethylation of the LINC00261 promoter were performed to explore the upstream epigenetic mechanisms and therapeutic potential. Results: LINC00261 was significantly downregulated in PC tissues, and its expression was positively associated with the prognosis of PC patients. Phenotypic studies indicated that LINC00261 overexpression significantly suppressed PC cell proliferation, migration and metastasis in vitro and in vivo . c-Myc was identified as a downstream target of LINC00261. LINC00261 repressed c-Myc transcription by physically interacting and binding with the bromo domain of p300/CBP, preventing the recruitment of p300/CBP to the promoter region of c-Myc and decreasing the H3K27Ac level. Moreover, the methylation level of the LINC00261 promoter was high in PC tissues and was correlated with poor prognosis. Targeted demethylation of the LINC00261 promoter inhibited PC progression both in vitro and in vivo . Conclusions: Our findings indicate that methylation-mediated LINC00261 suppresses PC progression by epigenetically repressing c-Myc expression. These findings expand the therapeutic potential of LINC00261, possibly providing evidence to support the development of epigenetic drugs or therapeutic strategies. This research adds further insights into the etiology of PC and indicates that LINC00261 may be a prognostic and therapeutic target in PC.

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“…The results of the current study displayed that silencing of HOTAIR promoted chemosensitivity to 5-FU and apoptosis while repressing cell proliferation and tumor growth in EC. In general, lncRNAs have been shown to be key mediators in chemoresistance, and lncRNA LINC00261 has been reported to significantly modulate the chemoresistance observed in 5-FU in human EC [22]. Lu et al have similarly shown that 5-FU could repress proliferation and induce the apoptosis of EC cells [5].…”

Section: Discussionmentioning

confidence: 99%

LncRNA HOTAIR-mediated MTHFR methylation inhibits 5-fluorouracil sensitivity in esophageal cancer cells

Zhang

Zheng

Zhang

et al. 2020

J Exp Clin Cancer Res

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Background: Esophageal cancer (EC) represents one of the most aggressive digestive neoplasms globally, with marked geographical variations in morbidity and mortality. Chemoprevention is a promising approach for cancer therapy, while acquired chemoresistance is a major obstacle impeding the success of 5-fluorouracil (5-FU)-based chemotherapy in EC, with the mechanisms underlying resistance not well-understood. In the present study, we focus on exploring the role of long non-coding RNA (lncRNA) HOTAIR in EC progression and sensitivity of EC cells to 5-FU. Methods: Paired cancerous and pre-cancerous tissues surgically resected from EC patients were collected in this study. Promoter methylation of the MTHFR was assessed by methylation-specific PCR. RIP and ChIP assays were adopted to examine the interaction of DNA methyltransferases (DNMTs) with lncRNA HOTAIR and MTHFR, respectively. EC cells resistant to 5-FU were induced by step-wise continuous increasing concentrations of 5-FU. The sensitivity of EC cells to 5-FU in vivo was evaluated in nude mice treated with xenografts of EC cells followed by injection with 5-FU (i.p.). Results: We found reciprocal expression patterns of lncRNA HOTAIR and MTHFR in EC tissues and human EC cells. Interference with lncRNA HOTAIR enhanced 5-FU-induced apoptosis, exhibited anti-proliferative activity, and reduced promoter methylation of the MTHFR in EC cells. Besides, overexpression of MTHFR attenuated the acquired chemoresistance induced by overexpression of lncRNA HOTAIR in EC cells. At last, enhanced chemosensitivity was observed in vivo once nude mice xenografted with lncRNA HOTAIR-depleted EC cells. Conclusion: Together, our study proposes that pharmacologic targeting of lncRNA HOTAIR sensitizes EC cells to 5-FU-based chemotherapy by attenuating the promoter hypermethylation of the MTHFR in EC.

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Long noncoding RNA LINC00261 induces chemosensitization to 5‐fluorouracil by mediating methylation‐dependent repression of DPYD in human esophageal cancer

Cited by 47 publications

References 32 publications

LINC00261 Is Differentially Expressed in Pancreatic Cancer Subtypes and Regulates a Pro-Epithelial Cell Identity

LINC00261 Is Differentially Expressed in Pancreatic Cancer Subtypes and Regulates a Pro-Epithelial Cell Identity

Methylation-mediated LINC00261 suppresses pancreatic cancer progression by epigenetically inhibiting c-Myc transcription

LncRNA HOTAIR-mediated MTHFR methylation inhibits 5-fluorouracil sensitivity in esophageal cancer cells

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