SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells

Abstract

Serine and arginine rich splicing factor 3 (SRSF3), an SR-rich family protein, has an oncogenic function in various kinds of cancer. However, the detailed mechanism of the function had not been previously clarified. Here, we showed that the SRSF3 splicer regulated the expression profile of the pyruvate kinase, which is one of the rate-limiting enzymes in glycolysis. Most cancer cells express pyruvate kinase muscle 2 (PKM2) dominantly to maintain a glycolysis-dominant energy metabolism. Overexpression of SRSF3, as well as that of another splicer, polypyrimidine tract binding protein 1 (PTBP1) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), in clinical cancer samples supported the notion that these proteins decreased the Pyruvate kinase muscle 1 (PKM1)/PKM2 ratio, which positively contributed to a glycolysis-dominant metabolism. The silencing of SRSF3 in human colon cancer cells induced a marked growth inhibition in both in vitro and in vivo experiments and caused an increase in the PKM1/PKM2 ratio, thus resulting in a metabolic shift from glycolysis to oxidative phosphorylation. At the same time, the silenced cells were induced to undergo autophagy. SRSF3 contributed to PKM mRNA splicing by co-operating with PTBP1 and hnRNPA1, which was validated by the results of RNP immunoprecipitation (RIP) and immunoprecipitation (IP) experiments. These findings altogether indicated that SRSF3 as a PKM splicer played a positive role in cancer-specific energy metabolism.

Targeting immunometabolism as an anti-inflammatory strategy

“…This event is highly regulated and in order to obtain mature PKM2 mRNA, both repression of exon 9, an event regulated by splicing factors PTB, hnRNPA1 and hnRNPA2, as well as the inclusion of exon 10 by SRSF3 are required. [132][133][134][135] PKM1 is expressed in most normal differentiated tissues as well as in resting inactive immune cells. PKM2 on the other hand is upregulated in activated immune cells such as LPS-activated macrophages and CD3/CD28 activated T cells.…”

Landscape of Cell Heterogeneity and Evolutionary Trajectory in Ulcerative Colitis-associated Colon Cancer Revealed by Single-cell Rna Sequencing

“…In cluster 2, we found that cytotoxic T cell-speci c genes, such as GZMA and GNLY, were highly expressed (32). Additionally, the glycolysis pathway was most highly expressed in cluster 2 among the three clusters, and a related gene, PKM, was also highly expressed (33). In cluster 3, we detected minor populations of cells expressing higher levels of the immune checkpoint molecule HAVCR, which acts in the tolerance and exhaustion of T cells (34) and is currently targeted in clinical trials of immunotherapy for cancers (35).…”

LINC00649 underexpression is an adverse prognostic marker in acute myeloid leukemia

“…Functional mutations of SRSF2 drive the cancer genesis of hematopoietic cells [43]. SRSF3 is a multiple cancer related splicing factor, namely glioblastoma [44], colon cancer [45], oral squamous carcinoma [46], etc. Moreover, the expression of SRSF2/3 is signi cantly decreased in de novo AML patients in comparison with that of healthy controls.…”