DIRAS3: An Imprinted Tumor Suppressor Gene that Regulates RAS and PI3K-driven Cancer Growth, Motility, Autophagy, and Tumor Dormancy

• Published in: Molecular cancer therapeutics Vol. 21; no. 1; pp. 25 - 37
• Main Authors: Bildik, Gamze, Liang, Xiaowen, Sutton, Margie N, Bast, Jr, Robert C, Lu, Zhen
• Format: Journal Article
• Language: English
• Published: United States 01.01.2022
• Subjects: Animals; Autophagy; Female; Genes, Tumor Suppressor - physiology; Humans; Mice; Phosphatidylinositol 3-Kinases - metabolism; ras Proteins - metabolism; Signal Transduction
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-21-0331

DIRAS3 is an imprinted tumor suppressor gene that encodes a 26 kDa GTPase with 60% amino acid homology to RAS, but with a distinctive 34 amino acid N-terminal extension required to block RAS function. DIRAS3 is maternally imprinted and expressed only from the paternal allele in normal cells. Loss of expression can occur in a single "hit" through multiple mechanisms. Downregulation of DIRAS3 occurs in cancers of the ovary, breast, lung, prostate, colon, brain, and thyroid. Reexpression of DIRAS3 inhibits signaling through PI3 kinase/AKT, JAK/STAT, and RAS/MAPK, blocking malignant transformation, inhibiting cancer cell growth and motility, and preventing angiogenesis. DIRAS3 is a unique endogenous RAS inhibitor that binds directly to RAS, disrupting RAS dimers and clusters, and preventing RAS-induced transformation. DIRAS3 is essential for autophagy and triggers this process through multiple mechanisms. Reexpression of DIRAS3 induces dormancy in a nu/nu mouse xenograft model of ovarian cancer, inhibiting cancer cell growth and angiogenesis. DIRAS3-mediated induction of autophagy facilitates the survival of dormant cancer cells in a nutrient-poor environment. DIRAS3 expression in dormant, drug-resistant autophagic cancer cells can serve as a biomarker and as a target for novel therapy to eliminate the residual disease that remains after conventional therapy.