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

Author:

Guo Yubin,Ye Qing,Deng PanORCID,Cao Yanan,He Daheng,Zhou Zhaohe,Wang Chi,Zaytseva Yekaterina Y.ORCID,Schwartz Charles E.ORCID,Lee Eun Y.,Evers B. MarkORCID,Morris Andrew J.ORCID,Liu Side,She Qing-BaiORCID

Abstract

AbstractDysregulation 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.

Funder

South Carolina Department of Disabilities and Special Needs Grant

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

U.S. Department of Health & Human Services | NIH | National Cancer Institute

U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences

Publisher

Springer Science and Business Media LLC

Subject

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

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