The human protein N(α)-terminal acetyltransferase A complex (hNatA), composed of the catalytic hNaa10p (hArd1) and auxiliary hNaa15p (hNat1/NATH/Tubedown) subunits, was reported to be important for cell survival and growth of various types of cancer. However, little is known about the mechanisms mediating growth inhibition and apoptosis following loss of hNatA function. Here, we have screened 11 different thyroid cell lines for hNAA10 RNAi phenotypes and observed mostly growth inhibition, which was independent of TP53 functional status and developed by several different mechanisms involving (i) downregulation of cyclin D1, (ii) increase in p27/Kip1 and (iii) inactivation of Rb/E2F pathway. hNatA depletion in aggressive thyroid cancer cell lines (8305C, CAL-62 and FTC-133) with mutated TP53 increased sensitivity to drug-induced cytotoxicity, but in a cell type specific manner: 8305C (TRAIL), CAL-62 (daunorubicin) and FTC-133 (troglitazone). Cells harboring wild-type TP53 were also prone to apoptosis via the p53 pathway after hNatA downregulation. Importantly, in hNatA-depleted cells DNA-damage signaling was activated in the absence of exogenous DNA damage independent on TP53 status. Our findings indicate that several mechanisms of growth inhibition and apoptosis may be induced by hNatA knockdown and that hNatA knockdown could be exploited for use in combinatorial chemotherapy.
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