The polyamine-hypusine circuit controls an oncogenic translational program necessary for MYC-driven lymphomagenesis

ABSTRACT: MYC oncogenes are activated in broad spectrum of human malignancies and transcriptionally reprogram the genome to drive cancer cell growth. Given this it is unclear if targeting a single effector will have a therapeutic benefit. MYC activates the polyaminehypusine circuit, which post-translationally modifies the translation factor eIF5A. The hypusine axis has been proposed to suppress tumorigenesis. Here we report essential roles for hypusinated eIF5A in the development and maintenance of Myc-driven lymphoma, where loss of eIF5A hypusination abolishes malignant transformation. Mechanistically, integrating RNA-seq, Ribo-seq and proteomic analyses revealed that efficient translation of select targets is dependent upon eIF5A hypusination, including key regulators of G1 to S phase cell cycle progression. Notably, this circuit controls Myc’s proliferative response at several levels, and it is activated across multiple tumor types. These findings suggest the hypusine circuit as a therapeutic target for a broad spectrum of malignancies.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, B Cell

DISEASE(S): Burkitt Lymphoma

SUBMITTER: John Koomen  

LAB HEAD: John Cleveland

PROVIDER: PXD031361 | Pride | 2024-01-26

REPOSITORIES: Pride