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

• Published in: Cell death & disease 2018-02, Vol.9 (2), p.149-15, Article 149
• Main Authors: Jiang, Weiliang, Zhao, Senlin, Shen, Jia, Guo, Lihong, Sun, Yi, Zhu, Yuntian, Ma, Zhixiong, Zhang, Xin, Hu, Yangyang, Xiao, Wenqin, Li, Kai, Li, Sisi, Zhou, Li, Huang, Li, Lu, Zhanjun, Feng, Yun, Xiao, Junhua, Zhang, Eric Erquan, Yang, Lijuan, Wan, Rong
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/2; 13/31; 13/51; 13/95; 3' Untranslated regions; 42/89; 64/60; Animals; Antibodies; ARNTL Transcription Factors - metabolism; Biochemistry; Bioinformatics; Biological Clocks; Biomedical and Life Sciences; BMAL1 protein; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemoresistance; Circadian rhythms; Drug Resistance, Neoplasm - genetics; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium; Feedback, Physiological; Gating; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Immunology; Life Sciences; Male; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplasm Invasiveness; Pancreatic cancer; Pancreatic Ducts - metabolism; Pancreatic Ducts - pathology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Prognosis; Transcription; Tumorigenesis; Tumors; YY1 Transcription Factor - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-017-0233-y

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.