SF3B4 promotes ovarian cancer progression by regulating alternative splicing of RAD52

Abstract

Many studies have proven that splicing factors are crucial for human malignant tumor development. However, as a classical splicing factor, the expression of SF3B4 is not clear, and its biological function needs to be further clarified in ovarian cancer (OC). We determined that SF3B4 was obviously upregulated and its high expression was associated with poor prognosis in OC patients. In vitro and in vivo assays suggested that SF3B4 overexpression promoted OC cell proliferation and mobility, and downregulation of SF3B4 had the opposite effect. Further studies found that miR-509–3p decreased SF3B4 mRNA expression by binding to the 3’ -UTR of SF3B4 directly. Importantly, we revealed that RAD52 was a potential target of SF3B4 through alternative splicing events analysis. Loss of SF3B4 led to decreased expression of RAD52, owing to intron 8 retention and generation of premature termination codons. Moreover, decreased expression of RAD52 partially counteracted the tumor-promoting effect of SF3B4 overexpression. In conclusion, our results suggested that SF3B4, negatively regulated by miR-509–3p, promoted OC progression through effective splicing of RAD52. Therefore, SF3B4 may be a promising biomarker and effective therapeutic target for OC.

SF3B4 promotes Twist1 expression and clear cell renal cell carcinoma progression by facilitating the export of KLF 16 mRNA from the nucleus to the cytoplasm

“…In recent years, more and more research has been conducted on SF3b4-related diseases such as Nagel syndrome and cancer [53]. Recently, Diao et al [54] found that SF3B4 promotes ovarian cancer progression by modulating alternative splicing of RAD52 [14]. SF3B4 is also closely related to the growth of non-small cell lung cancer cells.…”

“…Recent studies have revealed that SF3B4 plays important roles in the regulation of transcription, translation, and cell signaling in addition to pre-mRNA splicing. Importantly, emerging evidence suggests that the dysregulation of SF3B4 expression by gene mutations or other factors has been implicated in various diseases, including tumorigenesis and Nager syndrome (NS) [12][13][14]. For example, the upregulation of SF3B4 promotes tumorigenesis in hepatocellular carcinoma (HCC) [12], esophageal squamous cell carcinoma (ESCC) [13], and ovarian cancer (OC) [14], whereas its downregulation or depletion results in pancreatic cancer [15] and breast cancer in NS patient [16].…”

“…Importantly, emerging evidence suggests that the dysregulation of SF3B4 expression by gene mutations or other factors has been implicated in various diseases, including tumorigenesis and Nager syndrome (NS) [12][13][14]. For example, the upregulation of SF3B4 promotes tumorigenesis in hepatocellular carcinoma (HCC) [12], esophageal squamous cell carcinoma (ESCC) [13], and ovarian cancer (OC) [14], whereas its downregulation or depletion results in pancreatic cancer [15] and breast cancer in NS patient [16]. These findings indicate that SF3B4 plays distinct functional roles in different contexts and different cancer cells, strongly suggesting an essential role of SF3B4 in cell growth and the importance of a finely regulated level of SF3B4 for the regulation of cell homeostasis.…”

Parental mosaicism detection and preimplantation genetic testing in families with multiple transmissions of de novo mutations

“…The mutated gene SF3B4 in Family 2, encodes one of the components of the splicing factor 3b (SF3b) complex 32. The loss or gain of function caused by SF3b4 mutations is frequently associated with aberrant cell development and plays a role in the pathogenesis of various cancers including hepatocellular carcinoma, ovarian cancer and oesophagus squamous cell carcinoma 33–36. Whether SF3B4 plays a role in SSC self-renewal, leading to selfish spermatogonial selection, requires further investigation.…”

“…32 The loss or gain of function caused by SF3b4 mutations is frequently associated with aberrant cell development and plays a role in the pathogenesis of various cancers including hepatocellular carcinoma, ovarian cancer and oesophagus squamous cell carcinoma. [33][34][35][36] Whether SF3B4 plays a role in SSC self-renewal, leading to selfish spermatogonial selection, requires further investigation. Specifically, all different types of recurrence risk can be directly assessed by obtaining mosaicism VAF results from sperm sequencing analysis.…”