Dysregulation of polyamine metabolism has been linked to the development of colorectal cancer (CRC), but the underlying mechanism is incompletely characterized. Here, we report that spermine synthase (SMS), a polyamine biosynthetic enzyme, is overexpressed in CRC. Targeted disruption of SMS in CRC cells results in spermidine accumulation, which inhibits FOXO3a acetylation and allows subsequent translocation to the nucleus to transcriptionally induce expression of the proapoptotic protein Bim. However, this induction is blunted by MYC-driven expression of miR-19a and miR-19b that repress Bim production. Pharmacological or genetic inhibition of MYC activity in SMS-depleted CRC cells dramatically induces Bim expression and apoptosis and causes tumor regression, but these effects are profoundly attenuated by silencing Bim. These findings uncover a key survival signal in CRC through convergent repression of Bim expression by distinct SMS- and MYC-mediated signaling pathways. Thus, combined inhibition of SMS and MYC signaling may be an effective therapy for CRC.
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This work was supported by NCI grant R01CA203257, Start-Up funds (Q.-B.S.), pilot grants (Q.-B.S.) from CCSG P30CA177558 (University of Kentucky Markey Cancer Center) and CCTS UL1TR001998 (University of Kentucky), NIH/NIGMS grant P30GM127211 (A.J.M.), and a grant from the South Carolina Department of Disabilities and Special Needs (C.E.S.). This work was also supported in part by the Biospecimen Procurement and Translational Pathology, Cancer Research Informatics, Biostatistics and Bioinformatics, and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558).
The TCGA Colon Adenocarcinoma (TCGA-COAD) mRNA-sequencing data referenced during the study are available in a public repository from the GDC Data Portal (https://portal.gdc.cancer.gov/projects/TCGA-COAD). The raw microarray RNA-sequencing data “Skrzypczak Colorectal” and “Gaedcke Colorectal” are available from Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/gds/) with accession GSE20916 and GSE20842, respectively. The corresponding processed and normalized data are available from Oncomine (https://www.oncomine.org/). The source data underlying Figs. 1b–d, f–h, 2a–c, e–k, 3a, b, d–j, 4, 5a, c–e, g–n, 6, and 7a–c, e–l and Supplementary Figs. 1a, b, 2a, b, d, 3b–d, 4a–c, e, f, 5–7, 8a–g, 9, 10b, and 11b–d are provided as a Source Data file. All the other data supporting the findings of this study are available within the article and its supplementary information files and from the corresponding author upon reasonable request. A reporting summary for this article is available as a Supplementary Information file.
Guo, Yubin; Ye, Qing; Deng, Pan; Cao, Yanan; He, Daheng; Zhou, Zhaohe; Wang, Chi; Zaytseva, Yekaterina Y.; Schwartz, Charles E.; Lee, Eun Young; Evers, B. Mark; Morris, Andrew J.; Liu, Side; and She, Qing-Bai, "Spermine Synthase and MYC Cooperate to Maintain Colorectal Cancer Cell Survival by Repressing Bim Expression" (2020). Markey Cancer Center Faculty Publications. 150.