Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression

Yubin Guo, Qing Ye, Pan Deng, Yanan Cao, Daheng He, Zhaohe Zhou, Chi Wang, Yekaterina Y. Zaytseva, Charles E. Schwartz, Eun Y. Lee, B. Mark Evers, Andrew J. Morris, Side Liu () and Qing-Bai She ()
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Yubin Guo: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University
Qing Ye: Markey Cancer Center, University of Kentucky College of Medicine
Pan Deng: Superfund Research Center, University of Kentucky
Yanan Cao: Markey Cancer Center, University of Kentucky College of Medicine
Daheng He: Markey Cancer Center, University of Kentucky College of Medicine
Zhaohe Zhou: Markey Cancer Center, University of Kentucky College of Medicine
Chi Wang: Markey Cancer Center, University of Kentucky College of Medicine
Yekaterina Y. Zaytseva: Markey Cancer Center, University of Kentucky College of Medicine
Charles E. Schwartz: The Greenwood Genetic Center
Eun Y. Lee: Markey Cancer Center, University of Kentucky College of Medicine
B. Mark Evers: Markey Cancer Center, University of Kentucky College of Medicine
Andrew J. Morris: University of Kentucky College of Medicine, and Lexington Veterans Affairs Medical Center
Side Liu: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University
Qing-Bai She: Markey Cancer Center, University of Kentucky College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-17067-x

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