PDK4 Promotes Tumorigenesis Through Activation of CREB-RHEB-mTORC1 Signaling Cascade [Gene Regulation]

August 27th, 2014 by Liu, Z., Chen, X., Wang, Y., Peng, H., , Jing, Y., Zhang, H.

Mechanistic target of rapamycin (mTOR) integrates multiple extracellular and intracellular signals to regulate cell growth and survival. Hyperactivation of mTOR has been observed in various cancers. Regulation of mTOR activity is thus of importance in physiological processes and tumor development. Here we present pyruvate dehydrogenase kinase 4 (PDK4) as a novel regulator of mTORC1 signaling. mTORC1 activity was augmented with PDK4 overexpression and reduced by PDK4 suppression in various cell lines. Furthermore, PDK4 bound to cAMP response element-binding protein (CREB) and prevented its degradation. The enhanced CREB consequently transactivated the expression of Ras homolog enriched in brain (RHEB), a direct key activator of mTORC1, independent of AMP activated protein kinase or tuberous sclerosis complex protein 2. PDK4 potentiated mTORC1 effectors hypoxia-inducible factor 1-alpha and pyruvate kinase isozymes M2, and promoted aerobic glycolysis (Warburg effect). Knockdown of PDK4 suppressed the tumor development of cancer cells with activated mTORC1. The abundance of PDK4 dictated the responsiveness of cells to mTOR inhibitor, rapamycin. Combinatory suppression of mTOR and PDK4 exerted synergistic inhibition on cancer cell proliferation. Therefore PDK4 promotes tumorigenesis through activation of the CREB-RHEB-mTORC1 signaling cascade.