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

Yubin Guo1,2, Qing Ye2,3, Pan Deng4

  • 1Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.

Nature Communications
|June 28, 2020
PubMed

Insights

Overexpressed spermine synthase (SMS) and MYC pathways in colorectal cancer (CRC) converge to suppress the pro-apoptotic protein Bim. Inhibiting both SMS and MYC may offer a novel CRC therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Polyamines are crucial for cell growth, and their metabolism is often dysregulated in cancer.
  • The specific mechanisms linking polyamine metabolism to colorectal cancer (CRC) development require further elucidation.

Purpose of the Study:

  • To investigate the role of spermine synthase (SMS) in colorectal cancer (CRC) pathogenesis.
  • To identify signaling pathways that regulate the pro-apoptotic protein Bim in CRC.
  • To explore potential therapeutic strategies targeting SMS and MYC in CRC.

Main Methods:

  • Utilized genetic and pharmacological approaches to disrupt SMS and inhibit MYC activity in CRC cells.
  • Assessed changes in polyamine levels, protein acetylation, and gene/microRNA expression.
  • Evaluated the impact on Bim expression, apoptosis, and tumor regression in preclinical models.

Main Results:

  • Spermine synthase (SMS) is overexpressed in CRC, leading to spermidine accumulation.
  • SMS disruption promotes Bim-mediated apoptosis by inhibiting FOXO3a acetylation.
  • MYC-driven miR-19a/miR-19b represses Bim, counteracting SMS-disruption effects.
  • Combined inhibition of SMS and MYC significantly enhances Bim expression, apoptosis, and tumor regression.

Conclusions:

  • Convergent signaling pathways involving SMS and MYC regulate Bim expression in CRC.
  • Targeting both SMS and MYC simultaneously presents a promising therapeutic strategy for colorectal cancer.

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