Multiple mechanisms of HBx in promoting chromosome instability

Abstract

The hepatitis B virus X protein (HBx) encoded in HBV genome has been implicated in development of hepatocellular carcinoma (HCC) by promoting centrosome aberration and chromosomal instability. Evidences have shown that expression of HBx can cause centrosome over-amplification, but the molecular mechanism is not completely understood. Using stable HBx expressing clones, we observed that expression of HBx induced defects in centrosome ultrastructure and chromosome mis-segregation. Further investigation suggested that HBx bound to a centrosome protein called TAX1BP2, which was previously shown to be an intrinsic block of centrosome over-duplication. Restoring TAX1BP2 was found to block the effect of HBx in centrosome aberrations. Interestingly, we found that HBx also upregulated a novel mitotic gatekeeper PUMILIO-2 through down-regulation of its upstream inhibitor, a long non-coding RNA called NORAD, to promote chromosome instability. Dysregulation of NORAD was also found in clinical HCC samples. Thus, TAX1BP2 and PUMILIO-2 represent previously uncharacterized mechanisms of HBx to induce chromosome instability.