Aberrant alternative splicing facilitates cancer development and progression through both creating oncogenic isoforms and reducing normal isoforms. Serine/arginine-rich (SR) RNA binding protein family is one major class of splicing factors, which are concentrated in nuclear speckles and function critical roles in constitutive and alternative splicing. As a member of SR protein family, SRSF6 plays potential roles in some types of cancer such as skin, colon and lung.

Based on the previous work that long non-coding RNA LINC01133 inhibits epithelial-mesenchymal transition and metastasis in colorectal cancer by interacting with SRSF6, SRSF6 was frequently up-regulated in CRC samples and associated with poor prognosis, which promoted proliferation and metastasis in vitro and in vivo. Using next-generation sequencing, SRSF6-regulated AS targets and discover the SRSF6 binding motif were identified and validated. Particularly, SRSF6 regulates ZO-1 aberrant splicing to function as an oncogene by binding directly to its motif in the exon23. Based on the result that SRSF6 RRM2 domain plays key roles in regulating AS and biological function, indacaterol, a β2 adrenergic receptor agonist approved for chronic obstructive pulmonary disease (COPD) treatment, was identified as the inhibitor of SRSF6 to suppress CRC tumorigenicity.

These findings highlighted the functional importance of SRSF6 in mediating CRC progression through regulating AS. And these also provided strong pre-clinical evidence for repositioning indacaterol as an anti-tumor drug through targeting SRSF6.These results were published in the GUT online. The work was funded by the National Natural Science Foundation of China, the 111 Project and the Central University Fund.