Oncogenic lncRNAs alter epigenetic memory at a fragile chromosomal site in human cancer cells

Abstract

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.

Breaking the aging epigenetic barrier

“…Collectively these studies suggest a provocative, testable link between non-coding RNA, DNA methylation, altered gene expression and cancer progression. For example, we recently showed that when lncRNA PCAT2 gene is introduced to a naïve chromosome locus it acts in cis to mislocalize centromeric specific histone variant, thus altering the epigenetic memory and chromatin structure at the locus from where it was transcribed ( Arunkumar et al, 2022 ). LncRNAs can also interact with DNA to form RNA–DNA hybrids such as R-loops, to modulate chromatin architecture and accessibility of the transcription machinery to the underlying DNA.…”

Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis

“…Many lncRNAs function in regulating epigenetic modifications, some of which are also involved in the establishment of persistent epigenetic memory ( Arunkumar et al, 2022 ; Begolli et al, 2019 ; Fok et al, 2018 ; Wei et al, 2017 ). For example, recent work showed that transcription of locus 8q24-derived oncogenic lncRNAs such as PCAT2 could recruit centromeric protein-A (CENP-A), a variant of Histone H3, promote the ectopic localization of CENP-A, and alter epigenetic memory at a fragile chromosomal site in human cancer cells ( Arunkumar et al, 2022 ). In the current study, we investigated whether HOTAIR -mediated epigenetic alterations participate in enacting long-term epigenetic memory using transgenic iHOT + tumor cells.…”

Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis

“…Many lncRNAs function in regulating epigenetic modifications, some of which are also involved in the establishment of persistent epigenetic memory (Arunkumar et al, 2022; Begolli et al, 2019; Fok et al, 2019; Wei et al, 2017). For example, recent work showed that transcription of locus 8q24-derived oncogenic lncRNAs such as PCAT2 could recruit centromeric protein-A (CENP-A), a variant of Histone H3, promote the ectopic localization of CENP-A; and alter epigenetic memory at a fragile chromosomal site in human cancer cells (Arunkumar et al, 2022). In the current study, we investigated whether HOTAIR-mediated epigenetic alterations participate in enacting long-term epigenetic memory using transgenic iHOT + tumor cells.…”