DICER1 regulated let‐7 expression levels in p53‐induced cancer repression requires cyclin D1

Journal of Cellular and Molecular Medicine

Xin Sun³  Shou-Ching Tang⁴  Chongwen Xu³  Chenguang Wang²  Sida Qin³  Ning Du³  Jian Liu³  Yiwen Zhang³  Xiang Li³  Gang Luo³  Jie Zhou¹  Fei Xu⁵ 

[1] Department of Breast Oncology, Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China;Institute of Radiation Medicine, The Chinese Academy of Medical Sciences, Nankai District, Tianjin, China;Oncology Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China;Georgia Regents University Cancer Center, Augusta, GA, USA;Department of Radioation Oncology, Fudan University, Shanghai Cancer Center, Shanghai, China

关键词: let‐7;    regulatory loop;    cyclin D1;    DICER1;    cell apoptosis;    cancer stem cells;   

DOI  :  10.1111/jcmm.12522

来源: Wiley

【 摘 要 】

Abstract

Let-7 miRNAs act as tumour suppressors by directly binding to the 3′UTRs of downstream gene products. The regulatory role of let-7 in downstream gene expression has gained much interest in the cancer research community, as it controls multiple biological functions and determines cell fates. For example, one target of the let-7 family is cyclin D1, which promotes G0/S cell cycle progression and oncogenesis, was correlated with endoribonuclease DICER1, another target of let-7. Down-regulated let-7 has been identified in many types of tumours, suggesting a feedback loop may exist between let-7 and cyclin D1. A potential player in the proposed feedback relationship is Dicer, a central regulator of miRNA expression through sequence-specific silencing. We first identified that DICER1 is the key downstream gene for cyclin D1-induced let-7 expression. In addition, we found that let-7 miRNAs expression decreased because of the p53-induced cell death response, with deregulated cyclin D1. Our results also showed that cyclin D1 is required for Nutlin-3 and TAX-induced let-7 expression in cancer repression and the cell death response. For the first time, we provide evidence that let-7 and cyclin D1 form a feedback loop in regulating therapy response of cancer cells and cancer stem cells, and importantly, that alteration of let-7 expression, mainly caused by cyclin D1, is a sensitive indicator for better chemotherapies response.

【 授权许可】

CC BY   
© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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