Emerging Roles of SRSF3 as a Therapeutic Target for Cancer

Abstract

Ser/Arg-rich (SR) proteins are RNA-binding proteins known as constitutive and alternative splicing (AS) regulators that regulate multiple aspects of the gene expression program. Ser/Arg-rich splicing factor 3 (SRSF3) is the smallest member of the SR protein family, and its level is controlled by multiple factors and involves complex mechanisms in eukaryote cells, whereas the aberrant expression of SRSF3 is associated with many human diseases, including cancer. Here, we review state-of-the-art research on SRSF3 in terms of its function, expression, and misregulation in human cancers. We emphasize the negative consequences of the overexpression of the SRSF3 oncogene in cancers, the pathways underlying SRSF3-mediated transformation, and implications of potential anticancer drugs by downregulation of SRSF3 expression for cancer therapy. Cumulative research on SRSF3 provides critical insight into its essential part in maintaining cellular processes, offering potential new targets for anti-cancer therapy.

Keywords: RNA splicing; SRSF3; alternative splicing; cancer; oncogene.

Figure 1

Schematic diagram of gene expression in prokaryote cells.

Figure 2

SRSF3 regulates several cellular functions in eukaryote cells.

Figure 3

SRSF3 expression is regulated by several factors and signaling pathways.

Figure 4

The comprehensive mechanism of SRSF3 functions as an oncogene by regulating multiple splicing targets in cancer cells. On the one hand, SRSF3 can enhance cell proliferation, migration, invasion, metastasis, transformation, drug resistance, tumorigenesis, and energy metabolism. On the other hand, SRSF3 can inhibit cell cycle arrest, apoptosis, cellular senescence, and autophagy. SRSF3 is also involved in immunotherapy resistance, tumor microenvironment, cell homeostasis, and maintenance of HPV-related cancer.

Figure 5

The antitumor function of some drugs via decreasing the expression of SRSF3. Caffeine, digoxin, amiodarone, amiloride, and theobromine induce the apoptosis of cancer cells by decreasing the expression of SRSF3 and its downstream signaling cascade, including inducing the switch of p53 splicing from p53α to the p53β isoform. Moreover, theophylline and amiodarone could enhance caffeine-induced cell death, and amiodarone could also enhance the efficacy of digoxin.

Figure 6

The crosstalk between SRSF3 and other splicing regulators in the regulation of gene expression. There are antagonistic effects among SRSF3, SRSF1, and HnRNP L on alternative splicing or 5'ss selection, involving the key genes or signaling pathways, such as the Wnt/β-catenin pathway, MCC protein, and Rac1b.