PCBP1 inhibits the expression of oncogenic STAT3 isoform by targeting alternative splicing of STAT3 exon 23

Abstract

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.

Patient Characteristics Influence Activated Signal Transducer and Activator of Transcription 3 (STAT3) Levels in Primary Breast Cancer—Impact on Prognosis

“…It is possible that the pSTAT3 Y705 isoforms, primarily alpha and beta, differ between tumors with intermediate and high levels. These isoforms have different properties, and depending on the distribution of the two isoforms, pSTAT3 may either be tumor promoting or inhibiting ( 45 , 46 ). The interplay of pSTAT3 with other STATs ( 11 , 13 , 47 ), their negative feedback loops ( 1 , 48 ), and the tumor microenvironment ( 43 ) need to be assessed further.…”

Hsa_circ_0003998 promotes epithelial to mesenchymal transition of hepatocellular carcinoma by sponging miR-143-3p and PCBP1

“…Circ0003998 promotes the EMT in HCC cell through PCBP1/CD44v6 pathway Since PCBP1 is recognized as a tumor suppressor in previous studies [18][19][20], we hypothesized that function of PCBP1 could be inhibited when bind to circ0003998, which thereby promote EMT of HCC. Firstly, Gene Transcription Regulation Database (GTRD, http://gtrd.…”

STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

“…As mentioned above, PCBP1can regulate the proportion of STAT3α/STAT3β. PCBP1 inhibits oral squamous cell carcinoma cell growth and the expression of Bcl-xL and survivin, and it reverses the function of STAT3α [ 172 , 173 ]. Recently, phosphorodiamidate morpholino oligomers (morpholinos) were targeted to a splicing enhancer, and then STAT3α was specifically switched to STAT3β, which led to apoptosis and cell cycle arrest in breast cancer cells [ 166 ].…”