Androgen receptor splicing variant 7 (ARv7) promotes DNA damage response in prostate cancer cells.

In the treatment of patients with locally advanced prostate cancer (PCa), androgen deprivation therapy (ADT) significantly enhances the efficacy of radiotherapy by weakening the DNA damage response (DDR) pathway. Recently, several studies have suggested that androgen receptor splicing variants (ARvs) may mediate a compensatory DDR pathway when canonical androgen receptor (AR) signaling is inhibited, thus contributing to the resistance of some patients to this combinational treatment. However, the specific roles of certain ARvs as well as the detailed mechanism of how ARvs regulate the DDR are not well understood. Here, we demonstrated that AR splicing variant 7 (ARv7), which is the most abundant form of ARvs, significantly promotes the DDR of PCa cells under severe DNA damage independent of its parental AR by using the ionizing radiation (IR) and doxorubicin (Dox)-treated cell models. Mechanistically, ARv7 is sufficient to upregulate both the homologous recombination (HR) and the nonhomologous end joining (NHEJ) pathways by forming a positive regulatory loop with poly ADP-ribose polymerase 1 (PARP1). Moreover, the presence of ARv7 impairs the synergistic effect between AR antagonists and poly ADP-ribose polymerase (PARP) inhibitor, which has been recently shown to be a promising future treatment strategy for metastatic castration resistant prostate cancer (mCRPC). Combined, our data indicate that constitutively active ARv7 not only contributes to radioresistance after ADT, but may also serve as a potential predictive biomarker for assessing the efficacy of novel PARP inhibitor-based therapy in PCa.

Inhibition of TIGAR Increases Exogenous p53 and Cisplatin Combination Sensitivity in Lung Cancer Cells by Regulating Glycolytic Flux.

The metabolism and apoptosis of tumor cells are important factors that increase their sensitivity to chemotherapeutic drugs. p53 and cisplatin not only induce tumor cell apoptosis, but also regulate the tumor cell metabolism. The TP53-induced glycolysis and apoptosis regulator (TIGAR) can inhibit glycolysis and promote more glucose metabolism in the pentose phosphate pathway. We speculate that the regulation of the TIGAR by the combination therapy of p53 and cisplatin plays an important role in increasing the sensitivity of tumor cells to cisplatin. In this study, we found that the combined treatment of p53 and cisplatin was able to inhibit the mitochondrial function, promote mitochondrial pathway-induced apoptosis, and increase the sensitivity. Furthermore, the expression of the TIGAR was inhibited after a combined p53 and cisplatin treatment, the features of the TIGAR that regulate the pentose phosphate pathway were inhibited, the glucose flux shifted towards glycolysis, and the localization of the complex of the TIGAR and Hexokinase 2 (HK2) on the mitochondria was also reduced. Therefore, the combined treatment of p53 and cisplatin may modulate a glycolytic flux through the TIGAR, altering the cellular metabolic patterns while increasing apoptosis. Taken together, our findings reveal that the TIGAR may serve as a potential therapeutic target to increase the sensitivity of lung cancer A549 cells to cisplatin.

LncRNA HOTAIR Enhances Epithelial-to-mesenchymal Transition to Promote the Migration and Invasion of Liver Cancer by Regulating NUAK1 via Epigenetic Inhibition miR-145-5p Expression.

LncRNA HOTAIR play important roles in the epigenetic regulation of carcinogenesis and progression in liver cancer. Previous studies suggest that the overexpression of HOTAIR predicts poor prognosis. In this study, through transcriptome sequencing data and in vitro experiments, we found that HOTAIR were more highly expressed and there is significantly positive relationship between HOTAIR and NUAK1 in liver cancer tissues and cell lines. miR-145-5p was downregulated and showed negative correlation with HOTAIR and NUAK1. Transfect Sh-HOTAIR, LZRS-HOTAIR, miR-145 mimic, miR-145 inhibitor to change the expression of HOTAIR and miR-145-5p. The addition of HTH-01-015 inhibits the expression of NUAK1. HOTAIR knockdown, miR-145-5p upregulation and NUAK1 inhibition all repressed migration, invasion and metastasis and reversed the epithelial-to-mesenchymal transition in SNU-387 and HepG2 cells. We also showed that HOTAIR recruiting and binding PRC2 (EZH2) epigenetically represses miR-145-5p, which controls the target NUAK1, thus contributing to liver cancer cell-EMT process and accelerating tumor metastasis. Moreover, it is demonstrated that HOTAIR crosstalk with miR-145-5p/NUAK1 during epigenetic regulation. Our findings indicate that HOTAIR/miR-145-5p/NUAK1 axis acts as an EMT regulator and may be candidate prognostic biomarker and targets for new therapies in liver cancer.