No 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.

Long noncoding RNAs (lncRNAs) are heterogeneous group of transcripts that lack coding potential and have essential roles in gene regulations. Recent days have seen an increasing association of noncoding RNAs with human diseases, especially cancers. One interesting group of noncoding RNAs strongly linked to cancers are heterochromatic repetitive Satellite RNAs. Satellite RNAs are transcribed from pericentromeric heterochromatic region of the human chromosomes. Satellite II RNA, most extensively studied, is upregulated in wide variety of epithelial cancer. Similarly, alpha satellite is over expressed in BRCA1‐deficient tumors. Though much is known about alpha satellites and SatII repeats, little is known about Satellite III (SatIII) lncRNAs in human cancers. SatIII repeats, though transcriptionally silent in normal conditions is actively transcribed under condition of stress, mainly heat shock. In this study, we show that colon and breast cancer cells aberrantly transcribes SatIII, in a heat shock factor I (HSF1)‐independent manner. Our study also reveals that, the overexpression of SatIII RNA favors cancer cell survival by overriding chemo drug‐induced cell death. Interestingly, knockdown of SatIII sensitizes cells toward chemotherapeutic drugs. This sensitization is possibly mediated by restoration of p53 protein expression that 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.

Long noncoding RNAs (lncRNAs) are widely known for their regulatory function in transcriptional and posttranscriptional processes. The involvement of such non‐protein‐coding RNAs in nuclear organization and chromatin remodeling is often associated with an increased risk of human malignancies. In cancer, lncRNAs either promote cell survival or may act as a growth suppressor, thus conferring a key regulatory function other than their established role in fundamental cellular processes. Interestingly, lncRNAs interfere with the stages of apoptosis and related pathways involving p53. Many of these molecules either regulate or are regulated by p53 while mounting oncogenic events. Consequently, they may confer both prosurvival or proapoptotic functions depending upon the tissue type. Since the mechanism of cell death is bypassed in many human cancers, it has emerged that the lncRNAs are either overexpressed or knocked down to sensitize cells to apoptotic stimuli. Nonetheless, the abundant expression of lncRNAs in tumor cells renders them suitable targets for anticancer therapies. Although the role of lncRNAs in the p53 network and apoptosis has been independently defined, their interplay in activating p53‐target genes during cell cycle arrest remains unexplored. Thus, we have specifically reviewed the possible involvement of lncRNAs in the p53‐mediated apoptosis of human cancer cells. In particular, we summarize the growing evidence from individual studies and analyze whether lncRNAs are essential to facilitate apoptosis in a p53‐dependent manner. This may lead to the identification of p53‐associated lncRNAs that are suitable therapeutic targets or diagnostic/prognostic markers.

Oncogenesis involves continuous genetic alterations that lead to compromised cellular integrity and immortal cell fate. The cells remain under excessive stress due to endo‐ and exogenous influences. Human Satellite III long noncoding RNA (SatIII lncRNA) is a key regulator of the global cellular stress response, although its function is poorly explained in cancers. The principal regulator of cancer meshwork is tumor protein p53, which if altered may result in chemoresistance. The heat shock factor 1 (HSF1) being a common molecule between the oncogenic control and global cellular stress acts as an oncogene as well as transcribes SatIII upon heat shock. This prompted us to determine the structure of SatIII RNA and establish the association between SatIII‐HSF1‐p53. We determined the most stable structure of SatIII RNA with the least energy of − 115.7 kcal/mol. Also, we observed a possible interaction of p53 with SatIII and HSF1 using support vector machine (SVM) algorithm for predicting RNA‐protein interaction (RPI). Further, we employ the STRING database to understand if p53 is an interacting component of the nuclear stress bodies (nSBs). A precise inference was drawn from molecular docking which confirmed the interaction of SatIII‐HSF1‐p53, where a mutated p53 resulted in an altered DNA‐binding property with the SatIII molecule. This study being first of its kind infers p53 to be a possible integral component of the nSBs, which may regulate cellular stress response during cancer progression in the presence of HSF1 and SatIII. An extended research on the regulations of SatIII and p53 may open new avenues in the field of apoptosis in cancer and the early approach of molecular targeting.