RNA‐binding protein NONO promotes breast cancer proliferation by post‐transcriptional regulation of SKP2 and E2F8

• Published in: Cancer science 2020-01, Vol.111 (1), p.148-159
• Main Authors: Iino, Kaori, Mitobe, Yuichi, Ikeda, Kazuhiro, Takayama, Ken‐ichi, Suzuki, Takashi, Kawabata, Hidetaka, Suzuki, Yutaka, Horie‐Inoue, Kuniko, Inoue, Satoshi
• Format: Article
• Language: English
• Subjects: Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer therapies; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - genetics; Cloning; DNA microarrays; DNA-Binding Proteins - genetics; E2F protein; Endocrine therapy; Female; Gene expression; Gene Expression Regulation - genetics; Gene regulation; Humans; Immunoglobulins; Immunohistochemistry; Immunoprecipitation; Immunoprecipitation - methods; Kinases; MCF-7 Cells; Medical prognosis; NONO; Original; Pathophysiology; Polymerase chain reaction; post‐transcriptional regulation; Proteins; Repressor Proteins - genetics; RNA polymerase; RNA Processing, Post-Transcriptional - genetics; RNA, Messenger - genetics; RNA-binding protein; RNA-Binding Proteins - genetics; S-Phase Kinase-Associated Proteins - genetics; siRNA; Splicing; Therapeutic applications
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14240

The majority of breast cancers are primarily hormone‐sensitive and can be managed by endocrine therapy, although therapy‐resistant or hormone‐refractory cancers need alternative treatments. Recently, increasing attention is being paid to RNA‐binding proteins (RBP) in cancer pathophysiology. The precise role of RBP in breast cancer, however, remains to be clarified. We herein show that an RBP non‐POU domain‐containing octamer binding (NONO) plays a critical role in the pathophysiology of breast cancers regardless of their hormone dependency. Clinicopathological and immunohistochemical study of 127 breast cancer cases showed that NONO is a significant independent prognostic factor for breast cancer patients. Notably, siRNA‐mediated NONO knockdown substantially repressed the proliferation of both hormone‐sensitive MCF‐7 and hormone‐refractory MB‐MDA‐231 breast cancer cells. Integrative analysis combined with expression microarray and RIP‐sequencing (RNA immunoprecipitation‐sequencing) showed that NONO post‐transcriptionally regulates the expression of cell proliferation‐related genes by binding to their mRNAs, as exemplified by S‐phase‐associated kinase 2 and E2F transcription factor 8. Overall, these results suggest that NONO is a key regulator for breast cancer proliferation through the pre‐mRNA splicing of cell proliferation‐related genes and could be a potential new diagnostic and therapeutic target for advanced disease. The present study shows that Drosophila behavior human splicing family RNA‐binding protein NONO plays a critical role in breast cancer tumorigenesis. Clinicopathological study defines that NONO immunoreactivity significantly correlates with poor overall and distant disease‐free survival of breast cancer patients. Cell‐based experiments show that NONO contributes to breast cancer proliferation by regulating SKP2 and E2F8 expression at the post‐transcriptional level. Our findings provide a new cancer strategy by applying NONO as a potential diagnostic and therapeutic target for breast cancer.