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

Author

Listed:
  • Yubin Guo

    (Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University
    Markey Cancer Center, University of Kentucky College of Medicine)

  • Qing Ye

    (Markey Cancer Center, University of Kentucky College of Medicine
    Department of Pharmacology and Nutritional Sciences, 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
    Department of Pharmacology and Nutritional Sciences, 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
    Department of Biostatistics, University of Kentucky College of Public Health)

  • Yekaterina Y. Zaytseva

    (Markey Cancer Center, University of Kentucky College of Medicine
    Department of Toxicology and Cancer Biology, 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
    Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine)

  • B. Mark Evers

    (Markey Cancer Center, University of Kentucky College of Medicine
    Department of Surgery, 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
    Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine)

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.

Suggested Citation

  • 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 & Qing-Bai She, 2020. "Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17067-x
    DOI: 10.1038/s41467-020-17067-x
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