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

• Published in: Nature communications Vol. 11; no. 1; pp. 3243 - 16
• Main Authors: Guo, Yubin, Ye, Qing, Deng, Pan, Cao, Yanan, He, Daheng, Zhou, Zhaohe, Wang, Chi, Zaytseva, Yekaterina Y., Schwartz, Charles E., Lee, Eun Y., Evers, B. Mark, Morris, Andrew J., Liu, Side, She, Qing-Bai
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26-06-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/31; 13/44; 13/51; 13/89; 13/95; 14/19; 38; 38/15; 38/22; 38/23; 38/70; 38/77; 38/88; 38/90; 45; 631/67/1504/1885; 631/67/2327; 64/60; 82/29; 82/80; Acetylation; Acetylation - drug effects; Animals; Apoptosis; Apoptosis - drug effects; Azepines - pharmacology; Bcl-2-Like Protein 11 - metabolism; BIM protein; Cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Cell survival; Cell Survival - drug effects; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Down-Regulation - drug effects; Enzymes; Female; Forkhead Box Protein O3 - metabolism; FOXO3 protein; Gene Deletion; Gene Expression Regulation, Neoplastic - drug effects; Humanities and Social Sciences; Humans; Male; Metabolism; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Models, Biological; multidisciplinary; Myc protein; Polyamines; Polyamines - metabolism; Proteins; Proto-Oncogene Proteins c-myc - metabolism; Science; Science (multidisciplinary); Signaling; Spermidine; Spermine; Spermine synthase; Spermine Synthase - metabolism; Survival; Transcription; Translocation; Triazoles - pharmacology; Up-Regulation - drug effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17067-x

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.
Polyamine metabolism is frequently dysregulated in cancers. Here, the authors show that a polyamine biosynthetic enzyme, spermine synthase, is overexpressed in colorectal cancers and cooperates with MYC to prevent cancer cell apoptosis by repression of proapoptotic protein, Bim.