Long non-coding RNAs: An emerging powerhouse in the battle between life and death of tumor cells.

Long non-coding RNAs (lncRNAs) represent a class of non-protein coding transcripts longer than 200 nucleotides that have aptitude for regulating gene expression at the transcriptional, post-transcriptional or epigenetic levels. In recent years, lncRNAs, which are believed to be the largest transcript class in the transcriptomes, have emerged as important players in a variety of biological processes. Notably, the identification and characterization of numerous lncRNAs in the past decade has revealed a role for these molecules in the regulation of cancer cell survival and death. It is likely that this class of non-coding RNA constitutes a critical contributor to the assorted known or/and unknown mechanisms of intrinsic or acquired drug resistance. Moreover, the expression of lncRNAs is altered in various patho-physiological conditions, including cancer. Therefore, lncRNAs represent potentially important targets in predicting or altering the sensitivity or resistance of cancer cells to various therapies. Here, we provide an overview on the molecular functions of lncRNAs, and discuss their impact and importance in cancer development, progression, and therapeutic outcome. We also provide a perspective on how lncRNAs may alter the efficacy of cancer therapy and the promise of lncRNAs as novel therapeutic targets for overcoming chemoresistance. A better understanding of the functional roles of lncRNA in cancer can ultimately translate to the development of novel, lncRNA-based intervention strategies for the treatment or prevention of drug-resistant cancer.

Identification of the lncRNA, AK156230, as a novel regulator of cellular senescence in mouse embryonic fibroblasts.

Long noncoding RNAs (lncRNAs) have gained extensive attentions in recent years because of their potential importance in a variety of biological and pathological processes. In this study, we sought to explore the role of lncRNAs in cellular senescence. Here, we report that the lncRNA AK156230 was downregulated during replicative senescence in mouse embryonic fibroblasts (MEFs), and knockdown of AK156230 promotes a robust senescence phenotype, including increase in the numbers of the senescence-associated ß-galactosidase-positive cells, decrease of cell proliferation, accumulation of cells in the G2/M phase and reduction of autophagic activity. The cells with knockdown AK156230 expression also exhibited increased levels of p21, p53 and phosphorylated p53, and a decreased activity of CDK1. Moreover, rapamycin-induced autophagy offered cytoprotective effect and rescued cellular senescence in AK156230 knockdown cells. Gene expression profile showed that the dysregulation of autophagy and cell cycle genes contributed to the induction of cellular senescence after AK1561230 silencing. Taken together, these results suggest that downregulation of AK156230 is involved in the induction of cellular senescence through its roles in autophagy and cell cycle progression. Our study identifies AK156230 as a critical lncRNA that has a role in regulating cellular senescence in MEFs.

Identification of Sirtuin 3, a mitochondrial protein deacetylase, as a new contributor to tamoxifen resistance in breast cancer cells.

The current study reports a previously unappreciated role of Sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, in altering sensitivity of breast cancer cells to tamoxifen (Tam), a commonly used anti-estrogen agent. We showed that SIRT3 was significantly up-regulated at both mRNA and protein levels in the Tam-resistance human breast cancer cell line MTR-3, which was derived from MCF-7 line by continuous selective culture in the presence of 1µM of Tam for two years. We further demonstrated that SIRT3 was rapidly up-regulated in the sensitive MCF-7 cells following exposure to Tam. Transfection of MCF-7 cells with a SIRT3 expression plasmid decreased cellular sensitivity to Tam and blocked the Tam-induced apoptosis. Furthermore, silencing of SIRT3 expression in MTR-3 cells sensitized the resistant cells to Tam and enhanced apoptotic cell death. MTR-3 cells with silencing of SIRT3 expression showed increases in the mitochondrial content of ERß, ROS level and apoptosis. These results not only uncovered a new role for SIRT3 in cancer but also identified this mitochondrial protein deacetylase as a previously unrecognized factor that participates in regulation of Tam sensitivity in breast cancer cells. Thus, SIRT3 might be considered as a potential target for overcoming Tam resistance in treatment of breast cancer.

NAC1 and HMGB1 enter a partnership for manipulating autophagy.

Our recent study revealed a new role of nucleus accumbens-1 (NAC1), a transcription factor belonging to the BTB/POZ gene family, in regulating autophagy. Moreover, we found that the high-mobility group box 1 (HMGB1), a chromatin-associated nuclear protein acting as an extracellular damage associated molecular pattern molecule (DAMP), is the downstream executor of NAC1 in modulating autophagy. In response to stress such as therapeutic insults, NAC1 increases the expression, cytosolic translocation and release of HMGB1; elevated level of the cytoplasmic HMGB1 leads to activation of autophagy. The NAC1-HMGB1 partnership may represent a previously unrecognized pathway that regulates autophagy in response to various stresses such as chemotherapy.