Human Satellite III long non-coding RNA imparts survival benefits to cancer cells

Abstract

Long non-coding RNAs are heterogeneous group of transcripts that lack coding potential and have crucial roles in gene regulations. Recent days have seen an increasing association of non-coding RNAs with human diseases, especially cancers. Satellite III (SatIII) lncRNAs are transcribed from pericentromeric heterochromatic region of the human chromosome. Though transcriptionally silent in normal conditions, SatIII is actively transcribed under condition of stress, mainly heat shock. SatII repeat, another component of pericentromeric region of human chromosome, has been associated with wide variety of epithelial cancer. Overexpression of Satellite RNAs induces breast cancer in mice. Though much is known about Satellite RNAs, which includes alpha satellites and SatII repeats, however little is known about SatIII in human cancers. Hence we directed our study to understand the role of human Satellite III repeats in cancerous conditions. In the present study, we show that colon and breast cancer cells transcribe SatIII independent of heat shock, in an HSF1-independent manner. Our study also reveals that, overexpression of SatIII RNA favours cancer cell survival by overriding chemo drug-induced cell death. Knockdown of SatIII sensitizes cells towards chemotherapeutic drugs. SatIII transcript knockdown restores the expression of p53 protein, which in turn facilitates cell death. Heat shock however helps SatIII to continue with its pro-cell survival function. Our results, therefore suggest SatIII to be an important regulator of human cancers. Induction of SatIII is not only a response to the oncogenic stress but also facilitates cancer progression by a distinct pathway that is different from heat stress pathway.

Human Satellite 1 (HSAT1) analysis provides novel evidence of pericentromeric transcription

“…This comparison is particularly relevant because of the same tumor type of the analyzed cell lines. Such varying levels of transcription in similar cancer tissues question the premise of a analogous overexpression behavior for HSAT1 ncRNA (Bartonicek et al 2016; Chatterjee and Sengupta 2021), or at least presupposes a more complex regulatory scenario. This is especially true when comparing two cell lines derived from lung carcinomas, H1299 and H1975, the former expressing more than 1 million times more than MCF10A and the latter underexpressing HSAT1 (approximately half of MCF10A transcription).…”

“…By turn, (peri)centromeric transcription has been related with cancer (Ting et al 2011; Sanchez Calle et al 2018; Bury et al 2020; Nogalski and Shenk 2020; Chatterjee and Sengupta 2021). HSAT1 transcription was assessed in the same cell lines used for copy number analysis, yet with even more dissimilar results.…”

“…By turn, (peri)centromeric transcription has been related with cancer (Ting et al 2011;Sanchez Calle et al 2018;Bury et al 2020;Nogalski and Shenk 2020;Chatterjee and Sengupta 2021).…”

“…Many ncRNAs are transcriptionally dysregulated in disease states: in transcript levels, (Deveson et al 2017), and potentially in transcript processing, or both. Increased satDNA expression has been related with genomic instability (Chatterjee and Sengupta 2021). Whilst preserving chromosome integrity (Plohl et al 2008; Bierhoff et al 2014; Ershova et al 2019), tandem repeats can potentially represent beacons of instability in cancer genomes (de Lima et al 2021).…”

“…Centromeric αSAT (Alpha Satellite) transcripts in particular have been considered vital for kinetochore stabilization and centromere cohesion (Liu et al 2015; McNulty et al 2017; Smurova and De Wulf 2018; Chen et al 2021). The progressive description of pericentromeric HSAT2 and HSAT3 transcripts has elevated their status to essential in several cellular contexts (Eymery et al 2009a), like the formation and regulation of heterochromatin (Saksouk et al 2015; Johnson et al 2017), aging (Enukashvily et al 2007; Mendez-Bermudez et al 2021), response to stress (Jolly et al 2004; Goenka et al 2016; Ninomiya et al 2020), differentiation (Yandim and Karakülah 2019; Dobrynin et al 2020), and cancer (Hall et al 2017; Nogalski and Shenk 2020; Chatterjee and Sengupta 2021).…”