Séquestration nucléolaire des histones durant le traitement anticancer à l'inhibition du protéasome : un mécanisme inédit de régulation
post-traductionnelle, possiblement à l'origine de la mort cellulaire.
By degrading most of cellular proteins, the proteasome is positioned as a key regulator of the proteome, against which most tumors have a strong addiction, due to the protein imbalance that characterizes them. Although its inhibition has been shown to be a good anticancer strategy, it is still limited to blood cancers. Unfortunately, their treatment sooner or later becomes compromised by cellular resistance. This is why the elucidation of the mechanism of death involved could allow a better understanding of this resistance, which would in turn constitute the basis for a more effective treatment One of the most spectacular and early events to manifest during this treatment is the massive deubiquitylation of histone H2A on lysine (K) 119. A rather paradoxical positive correlation between this event, which is associated with gene expression, and cellular sensitivity to proteasome inhibition, has been noticed. This led to an interest in its biological significance. Cancer and primary cells have been used as systems for proteomic study by immunoblot and immunofluorescence, to analyze chromatin status and the spatio-temporal distribution of histones during proteasome inhibition. Chemical inhibitors, interfering RNAs and expression vectors have been used for this purpose. An impressive phenomenon occurring during the proteasome inhibition has been revealed. Indeed, a drastic drop in histones level on chromatin occurs simultaneously with the deubiquitylation of H2A-ub (K119). The proteasome being inhibited, these, and possibly histones synthesized in S phase, would undergo an irreversible translocation in the nucleoli before the onset of apoptosis. This phenomenon is replicated by various proteasome inhibitors and siRNA, and occurs in both cancer and primary cells, but not in resistant cells, which do not demonstrate deubiquitination of H2A-ub (K119). Furthermore, overexpression of exogenous histones has been shown to lead to their nucleolar translocation, and it is thought that the combination of proteasome inhibition with this overexpression could be lethal. Although mostly preliminary, the results would reveal a surprising mechanism of post-translational regulation of endogenous histones, which would be sequestered in nucleoli when not incorporated into chromatin. Indeed, inhibition of the proteasome causes a significant disruption of the chromatin for several hours. Due to the intrinsic cytotoxicity of free histones and to their great cellular abundance, these may well be the cause of the death induced by proteasome inhibition. Finally, as a major stress sensor, the nucleolus could be the starting point of the death signaling.
Cancer H2A-ub (K119) Histones Proteasome Resistance Biomarker Deubiquitylation Nucleoli Apoptosis