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; Qing Bai She

doi:10.1038/s41467-020-17067-x

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, Qing Bai She

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55 Scopus citations

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.

Original language	English
Article number	3243
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17067-x
State	Published - Dec 1 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

Funding

We thank the Markey Cancer Center’s Research Communication Office for assistance with manuscript preparation. This work was supported by NCI grant R01CA203257, Start-Up funds (Q.-B.S.), pilot grants (Q.-B.S.) from CCSG P30CA177558 (University of Kentucky Markey Cancer Center) and CCTS UL1TR001998 (University of Kentucky), NIH/NIGMS grant P30GM127211 (A.J.M.), and a grant from the South Carolina Department of Disabilities and Special Needs (C.E.S.). This work was also supported in part by the Biospecimen Procurement and Translational Pathology, Cancer Research Informatics, Biostatistics and Bioinformatics, and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558).

Funders	Funder number
Biospecimen Procurement and Translational Pathology
Cancer Research Informatics, and Biostatistics and Bioinformatics Shared Resource Facilities
NIH/NIGMS
South Carolina Department of Disabilities and Special Needs
National Childhood Cancer Registry – National Cancer Institute	P30CA177558, R01CA203257
National Institute of General Medical Sciences	P30GM127211
National Center for Advancing Translational Sciences (NCATS)	UL1TR001998
University of Kentucky
University of Kentucky Markey Cancer Center	CCTS UL1TR001998

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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10.1038/s41467-020-17067-x

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title = "Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression",

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.",

author = "Yubin Guo and Qing Ye and Pan Deng and Yanan Cao and Daheng He and Zhaohe Zhou and Chi Wang and Zaytseva, {Yekaterina Y.} and Schwartz, {Charles E.} and Lee, {Eun Y.} and {Mark Evers}, B. and Morris, {Andrew J.} and Side Liu and She, {Qing Bai}",

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AU - Wang, Chi

AU - Zaytseva, Yekaterina Y.

AU - Schwartz, Charles E.

AU - Lee, Eun Y.

AU - Mark Evers, B.

AU - Morris, Andrew J.

AU - Liu, Side

AU - She, Qing Bai

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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