Editors' ChoiceCancer

MAGE takes down a tumor suppressor

Sci. Signal.  24 Feb 2015:
Vol. 8, Issue 365, pp. ec40
DOI: 10.1126/scisignal.aaa9611

In response to energy stress, AMPK (5' adenosine monophosphate–activated protein kinase) suppresses growth-promoting pathways mediated by the kinase mTOR and promotes energy-producing pathways, such as autophagy. Reduced AMPK abundance is associated with tumor growth. Genes encoding melanoma antigens (MAGE) are generally silent in adult tissues except for the testis and are aberrantly expressed in cancer cells. Pineda et al. found that reactivation of a subset of MAGE-encoding genes promotes the degradation of AMPK in various cancers. Expression of genes encoding MAGE-A3 and MAGE-A6 (herein MAGE-A3/6) was restricted to the testis among various tissues in mice and humans, but MAGE-A3/6 were abundant in various human tumors and correlated with poor patient survival. Knocking down MAGE-A3/6 in cancer cell lines decreased cell proliferation and viability. Overexpressing MAGE-A3/6 promoted proliferation in mouse fibroblasts and anchorage-independent growth in colon cancer and nontransformed colonic epithelial cells. MAGE-A3/6 binds to and promotes the activity of the E3 ubiquitin ligase TRIM28. AMPKα1 was a substrate of a MAGE-TRIM28 complex in vitro. Knocking down MAGE-A3/6 or TRIM28 decreased the ubiquitylation of AMPKα1 in HeLa cells and increased the abundance of total and phosphorylated AMPKα1 without affecting its mRNA abundance. However, knocking down TRIM28 in MAGE-A3/6-negative cells had no effect on AMPKα1 abundance, and AMPKα1 bound to GST-tagged MAGE-A3/6 but not GST-TRIM28. Knocking down MAGE-A3/6 or TRIM28 suppressed mTOR activity and increased autophagy in an osteosarcoma cell line, but not in the presence of an AMPK inhibitor. In patient tumor tissues, high abundance of MAGE-A3/6 correlated with low abundance of AMPKα1 protein (but not mRNA) and increased abundance of markers of mTOR activity. The findings suggest that MAGE-A3/6 directs the ubiquitin-mediated degradation of AMPKα1 in tumor cells.

C. T. Pineda, S. Ramanathan, K. Fon Tacer, J. L. Weon, M. B. Potts, Y.-H. Ou, M. A. White, P. R. Potts, Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell 160, 715–728. [PubMed]