The functional role of a putative tumor suppressor protein, TAX1 binding protein 2(TAX1BP2) in hepatocellular carcinoma

Abstract

TAX1 binding protein 2 (TAX1BP2), which is a centrosomal protein, is first identified as a cellular interacting partner of human T-cell leukemia virus I (HTLV-I) encoded oncoprotein, TAX. Recently, TAX1BP2 was found to frequently underexpress in hepatocellular carcinoma (HCC) and underexpression of TAX1BP2 suppressed the level of an important tumor suppressor, p53 in a p38 MAPK dependent manner, strongly suggesting that TAX1BP2 is a putative tumor suppressor in HCC. TAX1BP2 is also involved in the chemo-sensitivity of HCC cells. We observed that the level of TAX1BP2 was significantly induced in HCC cells treated with the chemotherapeutic drugs, Cisplatin and Etoposide. To understand the role of TAX1BP2 in chemo-resistance, we demonstrated that TAX1BP2 was a phosphorylation substrate of a major DNA damage response kinase, called ATM and the phosphorylation of TAX1BP2 by ATM significantly modulated the protein level of TAX1BP2 via ubiquitination proteasomal degradation. In addition to the regulation by DNA damage response, we found that TAX1BP2 was also downregulated in cancer stem cell marker, CD133 positive cells, suggesting that TAX1BP2 may act downstream of CD133 signaling to regulate the chemo-sensitivity of HCC.