The Mechanism And Function Of SP Proteins In Regulating Wnt Signaling

Wnt/β-catenin signaling is widely implicated in embryogenesis, tissue homeostasis,stem cell self-renewal and tumorigenesis. The key event in Wnt signaling activation isβ-catenin accumulation, which is controlled by both its production and degradation. Themechanism mediating the control of β-catenin synthesis remain largely unknown, anissue we addressed by investigating a family of important RNA binding proteins, SRproteins (serine/arginine-rich splicing factors, SRSF). SR proteins play important rolesin controling gene expression, including transcription, splicing, mRNA nuclear export,mRNA stability and quality control. They are also involved in mRNA translation,maintenance of genomic stability as well as oncogenic transformation.Here, we show that the synthesis of β-catenin protein, which requires a group ofSR proteins, also contributes to its tumorigenic activity. Over-expression of SRSF1andSRSF9promote β-catenin accumulation via recruiting β-catenin mRNA and enhancingits translation in an mTOR-dependent manner. We further demonstrate that, like SRSF1,SRSF9is also an oncogene, and is frequently overexpressed in multiple types of humantumor samples. Moreover，β-catenin accumulation is partially required for the oncogenicactivity of SRSF1and SRSF9. Correspondingly, depletion of either SR proteins reduced coloncancer cell proliferation. Lastly, our results suggest that promoting degradation andblocking production of β-catenin synergistically reduce β-catenin level in colon cancercells and that a combinational therapy could be a promising approach for the treatmentof cancer patients with elevated β-catenin signaling.Together，our study establishes a novel link between the Wnt/β-catenin signalingand SR proteins: β-catenin is a major translational target of a subset of SR proteins,mediating their tumorigenic activity. These results deepen our understanding on themechanism and function of Wnt signaling. Furthermore, our work demonstrates theimportance of β-catenin synthesis during tumor progression and emphasizes thatpromoting degradation and blockage production of β-catenin protein should be equallyconsidered during therapeutic treatment of Wnt signaling-mediated tumors.