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.

多胺代谢失调与大肠癌（CRC）的发展有关，但其潜在机制尚不完整。在这里，我们报道精胺合成酶（SMS），一种多胺生物合成酶，在CRC中过表达。有针对性地破坏短信CRC细胞中的BMP导致亚精胺积累，从而抑制FOXO3a乙酰化，并随后转移至细胞核以转录诱导凋亡蛋白Bim的表达。然而，这种诱导被MYC驱动的抑制Bim产生的miR-19a和miR-19b的表达减弱。在SMS耗尽的CRC细胞中，MYC活性的药理或遗传抑制作用显着诱导Bim表达和凋亡，并导致肿瘤消退，但沉默Bim可以大大减弱这些作用。这些发现通过不同的SMS和MYC介导的信号传导通路对Bim表达的融合抑制，揭示了CRC中的关键生存信号。因此，联合抑制SMS和MYC信号可能是CRC的有效疗法。