STAT3 plays very important roles in the initiation and development of tumors. Despite of extensive studies in repressing its activation and function via multiple ways, so far, there are few effective therapeutic methods to inhibit STAT3 in the clinic. STAT3 has two isoforms generated by alternative splicing of exon 23. STAT3α is the longer isoform and encodes the full-length oncogenic STAT3α protein. STAT3β is shorter and encodes the truncated and tumor-suppressive STAT3β protein. It remains unknown how the alternative splicing of STAT3 exon 23 is regulated. Here, we discovered that there is an exonic splicing suppressor (ESS) in exon 23. Importantly, splicing factor PCBP1 binds to this ESS. Overexpression of PCBP1 significantly reduced the proportion of STAT3α /STAT3β isoforms and the expression of STAT3α protein. Moreover, increased PCBP1 inhibited the growth of oral squamous cell carcinoma and breast cancer cells, and the expression of STAT3 target genes. Our results demonstrated that PCBP1 is the key splicing factor that promotes the switch from oncogenic isoform STAT3α to tumor-suppressive isoform STAT3β. Our results pave the way for finding new anti-STAT3 methods for cancer treatment.

Inhibition of the expression of oncogene SRSF3 and cancer cell growth by blocking an exonic splicing suppressor in alternative exon 4 of SRSF3 with SR-3 antisense oligonucleotide.

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