Oncogenic lncRNAs alter epigenetic memory at a fragile chromosomal site in human cancer cells
Menée à l'aide d'une lignée cellulaire de cancer du côlon, cette étude met en évidence un mécanisme par lequel la transcription de longs ARNs non codants oncogènes altère les caractéristiques de la région chromosomique 8q24 en favorisant le recrutement d'un complexe comportant la protéine centromérique CENP-A, l'histone H3.3 et la protéine chaperon d'histone H3.3
Chromosome instability is a critical event in cancer progression. Histone H3 variant CENP-A plays a fundamental role in defining centromere identity, structure, and function but is innately overexpressed in several types of solid cancers. In the cancer background, excess CENP-A is deposited ectopically on chromosome arms, including 8q24/cMYC locus, by invading transcription-coupled H3.3 chaperone pathways. Up-regulation of lncRNAs in many cancers correlates with poor prognosis and recurrence in patients. We report that transcription of 8q24-derived oncogenic lncRNAs plays an unanticipated role in altering the 8q24 chromatin landscape by H3.3 chaperone–mediated deposition of CENP-A–associated complexes. Furthermore, a transgene cassette carrying specific 8q24-derived lncRNA integrated into a naïve chromosome locus recruits CENP-A to the new location in a cis-acting manner. These data provide a plausible mechanistic link between locus-specific oncogenic lncRNAs, aberrant local chromatin structure, and the generation of new epigenetic memory at a fragile site in human cancer cells.
Science Advances 2022