Splicing Regulator p54nrb/Non–POU Domain–Containing Octamer‐Binding Protein Enhances Carcinogenesis Through Oncogenic Isoform Switch of MYC Box–Dependent Interacting Protein 1 in Hepatocellular Carcinoma

Abstract

Background and Aims Alternative splicing (AS) is a key step that increases the diversity and complexity of the cancer transcriptome. Recent evidence has highlighted that AS has an increasingly crucial role in cancer. Nonetheless, the mechanisms underlying AS and its dysregulation in hepatocellular carcinoma (HCC) remain elusive. Here, we report that the expression of RNA‐binding protein p54nrb/non‐POU domain‐containing octamer‐binding protein (NONO) is frequently increased in patients with HCC and is associated with poor outcomes. Approach and Results Knockdown of NONO significantly abolished liver cancer cell proliferation, migration, and tumor formation. RNA‐sequencing revealed that NONO regulates MYC box–dependent interacting protein 1 (or bridging integrator 1 [BIN1]; also known as amphiphysin 2 3P9) exon 12a splicing. In the normal liver, BIN1 generates a short isoform (BIN1‐S) that acts as a tumor suppressor by inhibiting the binding of c‐Myc to target gene promoters. In HCC, NONO is highly up‐regulated and produces a long isoform (BIN1‐L, which contains exon 12a) instead of BIN1‐S. High levels of BIN1‐L promote carcinogenesis by binding with the protein polo‐like kinase 1 to enhance its stability through the prevention of ubiquitin/proteasome‐dependent cullin 3 degradation. Further analysis revealed that NONO promotes BIN1 exon 12a inclusion through interaction with DExH‐box helicase 9 (DHX9) and splicing factor proline and glutamine–rich (SFPQ). Notably, frequent coexpression of DHX9–NONO–SFPQ is observed in patients with HCC. Conclusions Taken together, our findings identify the DHX9–NONO–SFPQ complex as a key regulator manipulating the oncogenic splicing switch of BIN1 and as a candidate therapeutic target in liver cancer.

PRMT1 enhances oncogenic arginine methylation of NONO in colorectal cancer

“…Aberrant expression of NONO is correlated with malignant phenotypes in various cancers [32,33]. NONO increases lncRNA Prostate cancer gene expression marker (PCGEM)1 expression via upregulation of androgen receptor [34], resulting in castration-resistant prostate cancer [35].…”

Alternative RNA Splicing in Fatty Liver Disease

“…NONO-SFPQ is also the target for the lncRNA Morrbid and modulates Nras splicing (87). The NONO and SFPQ genes are frequently co-expressed in HCC where they promote the inclusion of exon12a in the bridging integrator 1 (BIN1) gene causing the expression of the BIN1-L isoform that binds and stabilizes PLK1 (88).…”

SFPQ promotes an oncogenic transcriptomic state in melanoma

“…Splicing factor proline-and glutamine-rich (SFPQ) is a multifunctional DNA-and RNA-binding protein that regulates numerous cellular mechanisms, including RNA-processing, transcription, DNA damage response and innate immunity [5][6][7][8][9]. Aberrant SFPQ function is associated with the aetiology of neurodegenerative disorders [10][11][12] and colorectal [13], hepatocellular [14], renal [15], Chronic Myeloid Leukaemia [16] and prostate cancer [17]. Intriguingly, it appears that SFPQ-long non-coding RNA (lncRNA) interactions are responsible for pathological changes in numerous cancers [14,15,18] including breast [19,20] and ovarian tumours [21].…”