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The MiR-135b-BMAL1-YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance.

ABSTRACT: Circadian disruption has been implicated in tumour development, but the underlying mechanism remains unclear. Here, we show that the molecular clockwork within malignant human pancreatic epithelium is disrupted and that this disruption is mediated by miR-135b-induced BMAL1 repression. miR-135b directly targets the BMAL1 3'-UTR and thereby disturbs the pancreatic oscillator, and the downregulation of miR-135b is essential for the realignment of the cellular clock. Asynchrony between miR-135b and BMAL1 expression impairs the local circadian gating control of tumour suppression and significantly promotes tumourigenesis and resistance to gemcitabine in pancreatic cancer (PC) cells, as demonstrated by bioinformatics analyses of public PC data sets and in vitro and in vivo functional studies. Moreover, we found that YY1 transcriptionally activated miR-135b and formed a 'miR-135b-BMAL1-YY1' loop, which holds significant predictive and prognostic value for patients with PC. Thus, our work has identified a novel signalling loop that mediates pancreatic clock disruption as an important mechanism of PC progression and chemoresistance.

SUBMITTER: Jiang W

PROVIDER: S-EPMC5833454 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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The MiR-135b-BMAL1-YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance.

Jiang Weiliang W Zhao Senlin S Shen Jia J Guo Lihong L Sun Yi Y Zhu Yuntian Y Ma Zhixiong Z Zhang Xin X Hu Yangyang Y Xiao Wenqin W Li Kai K Li Sisi S Zhou Li L Huang Li L Lu Zhanjun Z Feng Yun Y Xiao Junhua J Zhang Eric Erquan EE Yang Lijuan L Wan Rong R

Cell death & disease 20180202 2

Circadian disruption has been implicated in tumour development, but the underlying mechanism remains unclear. Here, we show that the molecular clockwork within malignant human pancreatic epithelium is disrupted and that this disruption is mediated by miR-135b-induced BMAL1 repression. miR-135b directly targets the BMAL1 3'-UTR and thereby disturbs the pancreatic oscillator, and the downregulation of miR-135b is essential for the realignment of the cellular clock. Asynchrony between miR-135b and ...[more]

PMID: 29396463

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Project description:BackgroundNF-κB signaling is widely linked to the pathogenesis and treatment resistance in cancers. Increasing attention has been paid to its anti-oncogenic roles, due to its key functions in cellular senescence and the senescence-associated secretory phenotype (SASP). Therefore, thoroughly understanding the function and regulation of NF-κB in cancers is necessary prior to the application of NF-κB inhibitors.MethodsWe established glioblastoma (GBM) cell lines expressing ectopic TCF4N, an isoform of the β-catenin interacting transcription factor TCF7L2, and evaluated its functions in GBM tumorigenesis and chemotherapy in vitro and in vivo. In p65 knock-out or phosphorylation mimic (S536D) cell lines, the dual role and correlation of TCF4N and NF-κB signaling in promoting tumorigenesis and chemosensitivity was investigated by in vitro and in vivo functional experiments. RNA-seq and computational analysis, immunoprecipitation and ubiquitination assay, minigene splicing assay and luciferase reporter assay were performed to identify the underlying mechanism of positive feedback regulation loop between TCF4N and the p65 subunit of NF-κB. A eukaryotic cell-penetrating peptide targeting TCF4N, 4N, was used to confirm the therapeutic significance.ResultsOur results indicated that p65 subunit phosphorylation at Ser 536 (S536) and nuclear accumulation was a promising prognostic marker for GBM, and endowed the dual functions of NF-κB in promoting tumorigenesis and chemosensitivity. p65 S536 phosphorylation and nuclear stability in GBM was regulated by TCF4N. TCF4N bound p65, induced p65 phosphorylation and nuclear translocation, inhibited its ubiquitination/degradation, and subsequently promoted NF-κB activity. p65 S536 phosphorylation was essential for TCF4N-led senescence-independent SASP, GBM tumorigenesis, tumor stem-like cell differentiation and chemosensitivity. Activation of p65 was closely connected to alterative splicing of TCF4N, a likely positive feedback regulation loop between TCF4N and p65 in GBM. 4N increased chemosensitivity, highlighting a novel anti-cancer strategy.ConclusionOur study defined key roles of TCF4N as a novel regulator of NF-κB through mutual regulation with p65 and provided a new avenue for GBM inhibition.

Dataset Information

The MiR-135b-BMAL1-YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance.

Publications

The MiR-135b-BMAL1-YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance.

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