RNA-binding protein (RBP) has a highly dynamic spatiotemporal regulation process and important biological functions. They are critical to maintain the transcriptome through post-transcriptionally controlling the processing and transportation of RNA, including regulating RNA splicing, polyadenylation, mRNA stability, mRNA localization, and translation. Alteration of each process will affect the RNA life cycle, produce abnormal protein phenotypes, and thus lead to the occurrence and development of tumors. Here, we summarize RBPs involved in tumor progression and the underlying molecular mechanisms whereby they are regulated and exert their effects. This analysis is an important step towards the comprehensive characterization of post-transcriptional gene regulation involved in tumor progression.

/pdf/rna-binding-proteins-in-tumor-progression-17fgfh4jy8.pdf

RNA-binding proteins in tumor progression

Abnormal alternative splicing (AS) caused by alterations to splicing factors contributes to tumor progression. Serine/arginine splicing factor 1 (SRSF1) has emerged as a key oncodriver in numerous solid tumors, leaving its roles and mechanisms largely obscure in glioma. Here, we demonstrate that SRSF1 is increased in glioma tissues and cell lines. Moreover, its expression was correlated positively with tumor grade and Ki-67 index, but inversely with patient survival. Using RNA-Seq, we comprehensively screened and identified multiple SRSF1-affected AS events. Motif analysis revealed a position-dependent modulation of AS by SRSF1 in glioma. Functionally, we verified that SRSF1 promoted cell proliferation, survival, and invasion by specifically switching the AS of the myosin IB (MYO1B) gene and facilitating the expression of the oncogenic and membrane-localized isoform, MYO1B-fl. Strikingly, MYO1B splicing was dysregulated in parallel with SRSF1 expression in gliomas and predicted the poor prognosis of the patients. Further investigation revealed that SRSF1-guided AS of the MYO1B gene increased the tumorigenic potential of glioma cells through the PDK1/AKT and PAK/LIMK pathways. Taken together, we identify SRSF1 as an important oncodriver that integrates AS control of MYO1B into promotion of gliomagenesis and represents a potential prognostic biomarker and target for glioma therapy.

Splicing factor SRSF1 promotes gliomagenesis via oncogenic splice-switching of MYO1B

Aberrant RNA splicing is recognized to contribute to cancer pathogenesis, but the underlying mechanisms remain mainly obscure. Here, we report that the splicing factor SRSF2 is upregulated frequently in human hepatocellular carcinoma (HCC), where this event is associated with poor prognosis in patients. RNA-seq and other molecular analyses were used to identify SRSF2-regulated alternative splicing events. SRSF2 binding within an alternative exon was associated with its inclusion in the RNA, whereas SRSF2 binding in a flanking constitutive exon was associated with exclusion of the alternative exon. Notably, cancer-associated splice variants upregulated by SRSF2 in clinical specimens of HCC were found to be crucial for pathogenesis and progression in hepatoma cells, where SRSF2 expression increased cell proliferation and tumorigenic potential by controlling expression of these variants. Our findings identify SRSF2 as a key regulator of RNA splicing dysregulation in cancer, with possible clinical implications as a candidate prognostic factor in patients with HCC. Cancer Res; 77(5); 1168–78. ©2017 AACR.

/pdf/srsf2-regulates-alternative-splicing-to-drive-hepatocellular-4dfm6wz42x.pdf

SRSF2 Regulates Alternative Splicing to Drive Hepatocellular Carcinoma Development

SIRT1 Regulates N 6 -Methyladenosine RNA Modification in Hepatocarcinogenesis by Inducing RANBP2-Dependent FTO SUMOylation

Effective DNA repair is essential for cell survival: a failure to correctly repair damage leads to the accumulation of mutations and is the driving force for carcinogenesis. Multiple pathways have evolved to protect against both intrinsic and extrinsic genotoxic events, and recent developments have highlighted an unforeseen critical role for RNA in ensuring genome stability. It is currently unclear exactly how RNA molecules participate in the repair pathways, although many models have been proposed and it is possible that RNA acts in diverse ways to facilitate DNA repair. A number of well-documented DNA repair factors have been described to have RNA-binding capacities and, moreover, screens investigating DNA-damage repair mechanisms have identified RNA-binding proteins as a major group of novel factors involved in DNA repair. In this review, we integrate some of these datasets to identify commonalities that might highlight novel and interesting factors for future investigations. This emerging role for RNA opens up a new dimension in the field of DNA repair; we discuss its impact on our current understanding of DNA repair processes and consider how it might influence cancer progression.

/pdf/the-roles-of-rna-in-dna-double-strand-break-repair-37xyfv3csf.pdf

The roles of RNA in DNA double-strand break repair.

SRSF1 Prevents DNA Damage and Promotes Tumorigenesis through Regulation of DBF4B Pre-mRNA Splicing

SRSF10 Plays a Role in Myoblast Differentiation and Glucose Production via Regulation of Alternative Splicing.

Cancer-associated cachexia (CAC) is a devastating syndrome characterized by progressive losses of adipose tissue and skeletal muscle. CAC-related adipose tissue loss (CAL) occurs early and is associated with a shorter survival time. To explore potential regulatory long noncoding RNAs (lncRNAs) of CAL, RNA microarrays were used to analyze the transcriptomes of white adipose tissue from CAC mice vs. control mice. A set of differentially expressed lncRNAs was identified, and among them was CAAlnc1, which suppressed adipogenesis of C3H10 cells as demonstrated by gain-of-function and loss-of-function experiments. RNA immunoprecipitation and pull-down assays revealed Hu antigen R (HuR) was an important binding partner of CAAlnc1. The interaction between CAAlnc1 and HuR blocked the binding of HuR to adipogenic transcription factor mRNAs and further downregulated the expression of these transcription factors. This study generated a list of CAL-related lncRNAs and provided details of a functional lncRNA which may play an important role in CAL.

Cachexia-related long noncoding RNA, CAAlnc1, suppresses adipogenesis by blocking the binding of HuR to adipogenic transcription factor mRNAs.

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SRSF2 Regulates Alternative Splicing to Drive Hepatocellular Carcinoma Development

SRSF1 Prevents DNA Damage and Promotes Tumorigenesis through Regulation of DBF4B Pre-mRNA Splicing

SRSF10 Plays a Role in Myoblast Differentiation and Glucose Production via Regulation of Alternative Splicing.

Cachexia-related long noncoding RNA, CAAlnc1, suppresses adipogenesis by blocking the binding of HuR to adipogenic transcription factor mRNAs.