The tumor suppressor gene WWOX links the canonical and noncanonical NF-κB pathways in HTLV-I Tax-mediated tumorigenesis

Both the canonical and noncanonical nuclear factor kappa B (NF-kappa B) pathways have been linked to tumorigenesis. However, it remains unknown whether and how the 2 signaling pathways cooperate during tumorigenesis. We report that inhibition of the noncanonical NF-kappa B pathway significantly delays tumorigenesis mediated by the viral oncoprotein Tax. One function of noncanonical NF-kappa B activation was to repress expression of the WWOX tumor suppressor gene. Notably, WWOX specifically inhibited Tax-induced activation of the canonical, but not the noncanonical NF-kappa B pathway. Mechanistic studies indicated that WWOX blocked Taxinduced inhibitors of kappa B kinase alpha (IKK alpha) recruitment to RelA and subsequent RelA phosphorylation at S536. In contrast, WWOX Y33R, a mutant unable to was to repress expression of the WWOX tumor suppressor gene. Notably, WWOX specifically inhibited Tax-induced activation of the canonical, but not the noncanonical NF-kappa B pathway. Mechanistic studies indicated that WWOX blocked Tax-induced inhibitors of kappa B kinase alpha (IKK alpha) recruitment to RelA and subsequent RelA phosphorylation at S536. In contrast, WWOX Y33R, a mutant unable to block the IKK alpha recruitment and RelA phosphorylation, lost the ability to inhibit Tax-mediated tumorigenesis. These data provide one important mechanism by which Tax coordinates the 2 NF-kappa B pathways for tumorigenesis. These data also suggest a novel role of WWOX in NF-kappa B regulation and viral tumorigenesis. (Blood. 2011; 117(5): 1652-1661)