Splicing factor SRSF1 promotes breast cancer progression via oncogenic splice switching of PTPMT1

Abstract

Background Intensive evidence has highlighted the effect of aberrant alternative splicing (AS) events on cancer progression when triggered by dysregulation of the SR protein family. Nonetheless, the underlying mechanism in breast cancer (BRCA) remains elusive. Here we sought to explore the molecular function of SRSF1 and identify the key AS events regulated by SRSF1 in BRCA. Methods We conducted a comprehensive analysis of the expression and clinical correlation of SRSF1 in BRCA based on the TCGA dataset, Metabric database and clinical tissue samples. Functional analysis of SRSF1 in BRCA was conducted in vitro and in vivo. SRSF1-mediated AS events and their binding motifs were identified by RNA-seq, RNA immunoprecipitation-PCR (RIP-PCR) and in vivo crosslinking followed by immunoprecipitation (CLIP), which was further validated by the minigene reporter assay. PTPMT1 exon 3 (E3) AS was identified to partially mediate the oncogenic role of SRSF1 by the P-AKT/C-MYC axis. Finally, the expression and clinical significance of these AS events were validated in clinical samples and using the TCGA database. Results SRSF1 expression was consistently upregulated in BRCA samples, positively associated with tumor grade and the Ki-67 index, and correlated with poor prognosis in a hormone receptor-positive (HR+) cohort, which facilitated proliferation, cell migration and inhibited apoptosis in vitro and in vivo. We identified SRSF1-mediated AS events and discovered the SRSF1 binding motif in the regulation of splice switching of PTPMT1. Furthermore, PTPMT1 splice switching was regulated by SRSF1 by binding directly to its motif in E3 which partially mediated the oncogenic role of SRSF1 by the AKT/C-MYC axis. Additionally, PTPMT1 splice switching was validated in tissue samples of BRCA patients and using the TCGA database. The high-risk group, identified by AS of PTPMT1 and expression of SRSF1, possessed poorer prognosis in the stage I/II TCGA BRCA cohort. Conclusions SRSF1 exerts oncogenic roles in BRCA partially by regulating the AS of PTPMT1, which could be a therapeutic target candidate in BRCA and a prognostic factor in HR+ BRCA patient.

The Immunohistochemical Expression of the Serine and Arginine-Rich Splicing Factor 1 (SRSF1) Is a Predictive Factor of the Recurrence of Basal Cell Carcinoma: A Preliminary Study on a Series of 52 Cases

“…SRSF1 is a splicing factor that also plays a proto-oncogene role by stimulating angiogenesis, cell growth, and cell proliferation [21][22][23]. Its oncogenic role has been characterized in numerous human cancers [12][13][14][15][16][17][18][21][22][23]. It has been found to be downregulated in unaffected brain parenchyma, as compared to human glioblastoma tissue, where it appears to influence tumor angiogenesis by stimulating the formation of the proangiogenic form of the vascular endothelial growth factor A (VEGFA) [14].…”

“…SRSF1 also exhibits several oncogenic functions, including the stimulation of angiogenesis, cell growth, and cell proliferation [12][13][14]. It has been found to be upregulated in numerous human malignancies, such as glioblastoma and breast carcinoma, as well as lung and colorectal cancer [12][13][14][15][16]. Recently, our research group also reported the poor prognostic role of SRSF1 in adult diffuse gliomas, prostate cancer, and mesotheliomas [17,18].…”

The Clinical Role of SRSF1 Expression in Cancer: A Review of the Current Literature

“…regulating the mitotic landscape [27]. SRSF1 also plays a direct role in promoting oncogenic pathways, in fact, in 2021 a study revealed that in breast cancer it is involved in alternative splicing promoting the overexpression of PTPMT1, which is related to breast cancer tumorigenesis through the P-AKT/C-MYC pathway [28].…”

Targeting Splicing Factor SRSF6 for Cancer Therapy

“…Ubiquitination is an important regulatory mechanism of protein stability mediated by the ubiquitin-proteasome system ( Hershko, 1983 ). Several splicing factors have been found to be ubiquitinated and then degraded by proteasome ( Du et al, 2021 ). LncRNA can directly regulate SRSF6 protein stability or function.…”