by H. Lee Moffitt Cancer Center & Research Institute

Activation of the polyamine-hypusine circuit is a hallmark of human cancer and of MYC-driven lymphoma. A, Copy number alterations (CNA) of EIF5A and EIFA2 (left), and of DHPS and DOHH (right) across different cancer types. Abbreviations for the indicated TCGA datasets are: prostate = PRAD; Liver Hepatocellular = LIHC; Diffuse Large Bcell Lymphoma = DLBC; Uterine Carcinosarcoma = UCS; Esophageal = SCA; Ovarian serous carcinoma = OV; Colorectal = COAD; Stomach = STAD; Rectum = READ; Bladder Urothelial = BLCA; Lung adenocarcinoma = LUAD; Adrenocortical carcinoma = ACC; Acute Myeloid Leukemia = LAML; Thymoma = THYM; Sarcoma = SARC; Uterine Corpus Endometrial = UCEC; Cervical carcinoma = CESC; Pheochromocytoma and Paraganglioma = PCPG; Pancreatic adenocarcinoma = PAAD; Skin Cutaneous Melanoma = SKCM; Breast = BRCA; Lung Squamous = LUSC; Thyroid = THCA; Lower Grade Glioma = LGG; Head & Neck Squamous = HNSC; Kidney Renal Papillary = KIRP; Cholangiocarcinoma = CHOL; Glioblastoma = GBM; Kidney Chromophobe = KICH; Kidney Renal Clear Cell = KIRC; Mesothelioma = MESO; Testicular Germ Cell Tumors = TGCT; and Uveal Melanoma = UVM. B, DHPS and DOHH levels in RNA-seq datasets in 17 cancer types derived from TCGA PanCanAtlas. Significance (by Mann-Whitney test): **** p<0.0001, *** p<0.001, ** p<0.01, * p<0.05. C, Correlation analysis between MYC expression and the expression of genes in the polyamine-hypusine pathway across different cancer types (TCGA). Size of circles indicate the degree of significance of the correlation. D, Expression profiling of arrays showing human genes in the hypusine axis, comparing expression in Burkitt lymphoma (BL) and normal B cell subsets (GSE12453). Rows represent different probe sets. E, Expression profiling of arrays showing the top 20 differentially expressed genes that are manifest in BL versus normal B cell subsets (GSE12453). Levels of significance determined by Mann-Whitney test (B) or unpaired t tests (D) and (E) are indicated as follows: *, p < 0.05; **, p < 0.01; ***, p< 0.001; ****, p < 0.0001. Credit: Blood Cancer Discovery (2023). DOI: 10.1158/2643-3230.BCD-22-0162

MYC proteins are important regulators of cancer cell growth, proliferation and metabolism through their ability to increase the expression of proteins involved in these processes. Deregulation of MYC proteins occurs in more than half of all cancers and is associated with poor patient prognosis and outcomes. Numerous researchers have devoted significant efforts to try to target MYC proteins as a therapeutic approach to treat cancer. However, this has been extremely challenging to date, and other complementary strategies are being investigated.

In a new article in Blood Cancer Discovery, which was published simultaneously with a presentation at the American Association for Cancer Research annual meeting 2023, a team of Moffitt Cancer Center researchers demonstrated a possible alternative approach. They showed that MYC activates a downstream pathway that chemically modifies a protein called eIF5A, and that inhibition of this modification process prevents lymphoma development and progression in mouse models.

"Our team hypothesized that rather than targeting MYC directly, it may be possible to inhibit its cancer effects by targeting a protein downstream of the MYC effector protein that is also critical to cancer development," said Shima Nakanishi, Ph.D., lead study author and research scientist in the Tumor Biology Department at Moffitt. "We focused our efforts on the polyamine biosynthesis pathway that is involved in cell growth and survival and that is hyper altered in many cancers."

The Moffitt team showed that MYC induces the expression of eIF5A and an enzyme called DHPS that modifies eIF5A with a unique amino acid called hypusine. The Moffitt researchers wanted to test if this chemical modification of eIF5A is important for the development and maintenance of lymphoma.

They conducted laboratory experiments with cell lines and mouse models and determined that hypusine-modified eIF5A is critical to the development of lymphomas that are regulated by MYC. When the researchers blocked this modification genetically or chemically by targeting eIF5A or DHPS, lymphoma development and progression were inhibited. Mechanistically, they discovered that hypusine-modified eIF5A was important for the production of proteins responsible for cell growth and DNA replication.

This is the first study to conclusively demonstrate that this modification is important to the development of cancer.

"As activation of the hypusine circuit is a hallmark of MYC-driven tumors, the development of improved small molecule inhibitors of DHPS, or of agents that bind to and block eIF5A-hypusine function, are attractive therapeutic strategies for translating these findings into the clinic," said study author John Cleveland, Ph.D., center director and chief scientific officer at Moffitt.

More information: Shima Nakanishi et al, The polyamine-hypusine circuit controls an oncogenic translational program essential for malignant conversion in MYC-driven lymphoma, Blood Cancer Discovery (2023). DOI: 10.1158/2643-3230.BCD-22-0162

Provided by H. Lee Moffitt Cancer Center & Research Institute