The UPR Transducer IRE1 Promotes Breast Cancer Malignancy by Degrading Tumor Suppressor microRNAs
Kezhong Zhang,
Hui Liu,
Zhenfeng Song,
Yuanyuan Jiang,
Hyunbae Kim,
Lobelia Samavati,
Hien M. Nguyen,
Zeng-Quan Yang
Affiliations
Kezhong Zhang
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI 48201, USA; Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA; Corresponding author
Hui Liu
Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
Zhenfeng Song
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
Yuanyuan Jiang
Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
Hyunbae Kim
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
Lobelia Samavati
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA; Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI 48201, USA
Hien M. Nguyen
Department of Chemistry, Wayne State University, Detroit, MI 48202, USA
Zeng-Quan Yang
Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA; Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA; Corresponding author
Summary: Dysregulation of inositol-requiring enzyme 1 (IRE1), the primary transducer of Unfolded Protein Response (UPR), has been observed in tumor initiation and progression, but the underlying mechanism remains to be further elucidated. In this study, we identified that the IRE1 gene is frequently amplified and over-expressed in aggressive luminal B breast cancer cells and that IRE1 upregulation is significantly associated with worse overall survival of patients with breast cancer. IRE1 processes and mediates degradation of a subset of tumor suppressor microRNAs (miRNAs), including miR-3607, miR-374a, and miR-96, via a mechanism called Regulated IRE1-Dependent Decay (RIDD). IRE1-dependent degradation of tumor suppressor miR-3607 leads to elevation of RAS oncogene GTPase RAB3B in breast cancer cells. Inhibition of IRE1 endoribonuclease activity with the pharmacological compound 4μ8C or genetic approaches effectively suppresses luminal breast cancer cell proliferation and aggressive cancer phenotypes. Our work revealed the IRE1-RIDD-miRNAs pathway that promotes malignancy of luminal breast cancer.
