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

Abstract

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.

Roles of Splicing Factors in Hormone-Related Cancer Progression

“…In terms of prostate cancer, the expression of NONO is upregulated in CRPC and metastatic prostate cancers, and increased expression of NONO associates with poor prognosis of prostate cancer patients [64]. These data suggest that NONO plays a key role in the progression of both breast and prostate cancers [64,74].…”

“…It is recently indicated that high-NONO immunoreactivity associates with poor prognosis of breast cancer patients [74]. Public breast cancer databases also show that NONO mRNA expression is increased in invasive ductal breast cancer compared to normal breast samples, and higher expression of NONO mRNA associates with poor distant disease-free and overall survivals of the patients with all subtypes and ER-positive subtype of breast cancers [74]. In terms of prostate cancer, the expression of NONO is upregulated in CRPC and metastatic prostate cancers, and increased expression of NONO associates with poor prognosis of prostate cancer patients [64].…”

NONO and tumorigenesis: More than splicing

“…Emerging evidence has demonstrated that NONO is overexpressed in various kinds of cancers, including bladder cancer, lung cancer, prostate cancer and ESCC . Furthermore, NONO protein level is an independent prognostic factor for some cancers . By contrast, NONO is usually down‐regulated in ER (oestrogen receptor)‐negative breast cancer.…”

Plasticity as an Underlying Mechanism of Tumor Heterogeneity in Breast Cancer

“…Patients that had higher expression of E2F8 showed significantly poorer prognosis [77]. Additionally it has been recently shown that post-transcriptional regulation of E2F8 by RNA binding proteins in breast cancer cell lines, increases the proliferative capabilities of breast cancer [78]. It is clear that E2F8 overexpression increases the invasive properties of breast cancer and results in poorer prognosis of breast cancer patients when overexpressed.…”