Inhibitors of histone deacetylase arrest cell cycle and induce apoptosis in cervical carcinoma cells circumventing human papillomavirus oncogene expression

Histone deacetylase (HDAC) inhibitors sodium butyrate and trichostatin A ar rest human papillomavirus (HPV)positive carcinoma cells in G1 to S transiti on of the cell cycle, which is paralleled by an up-regulation of the cyclin -dependent kinase inhibitors (CKIs) p21(CIP1) and p27(KIP1) as well as the complete loss of cdk2 activity. Although HPV expression was hitherto though t to be required to maintain a proliferative phenotype of these cells, cdk2 suppression is achieved even in the presence of ongoing viral transcriptio n. While CKIs normally cannot exert their cdk2-inhibitory function in the p resence of the viral oncoprotein E7, co-immunoprecipitation experiments rev ealed that E7 binding is prevented. Increase of p27(KIP1) correlates with d own-regulation of p45(SKP2), a component of the ubiquitin-protein ligase SC FSKP2 controlling the half-life of regulatory proteins during the cell cycl e. HDAC inhibition also triggered an E7-dependent degradation of pRb, while the levels of E2F remained unaffected. The presence of free intracellular E2F and the concomitant up-regulation of CKIs during G1 arrest results in a 'conflicting growth situation', which finally renders the cells to undergo apoptosis. These data provide novel molecular insights into how the transf orming potential of HPV can be bypassed and open new therapeutical perspect ives for the treatment of cervical cancer.