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Abstract

A considerable proportion of the human genome consists of transposable elements, including the long terminal repeats (LTRs) of endogenous retroviruses. During evolution, such LTRs were occasionally inserted upstream of protein-coding genes, contributing to their regulation. We previously identified the LTR12 from endogenous retrovirus 9 (ERV9) as a regulator of proapoptotic genes such as TP63 or TNFRSF10B. The promoter activity of LTR12 is largely confined to the testes, silenced in testicular carcinoma, but reactivated in testicular cancer cells by broad-range histone deacetylase (HDAC) inhibitors. Here we show that inhibition of HDAC1-3 is sufficient for LTR12 activation. Importantly, HDAC inhibitors induce LTR12 activity not only in testicular cancer cells, but also in cells derived from many additional tumor species. Finally, we characterize the transcription factor NF-Y as a mediator of LTR12 promoter activity and HDAC inhibitor-induced apoptosis, in the context of widespread genomic binding of NF-Y to specific LTR12 sequences. Thus, HDAC inhibitor-driven LTR12 activation represents a generally applicable means to induce proapoptotic genes in human cancer cells.

<p>The lncRNA LINC01194/miR-486-5p Axis Facilitates Malignancy in Non-Small Cell Lung Cancer via Regulating CDK4</p>

“…44 Studies have found that the oncogene CDK4, which plays a critical role in the progression of the cell cycle, is directly targeted by miR-486-5p, and mir-486-5p can inhibit non-small cell lung cancer by downregulating the expression of CDK4. 45 In this study, it was found that CDK4 was a potential target of miR-486-5p and that miR-486-5p regulated its expression by targeting the 3ʹUTR of the CDK4 gene. In addition, miR-486-5p overexpression reduced CDK4 expression, and co-transfection of shLINC011948, and miR-486-5p mimicked partially the effect of sh-LINC011948 on CDK4 protein levels.…”

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

“…34,39 We investigated if cell surface expression of PD-L1 in prostate and NSCL cancer cell lines was altered by HDAC inhibitor treatment. In two out of four cancer cell lines, H460 and DU145, exposure to vorinostat increased the fold change of the gMFI and percentage of cells with PD-L1 expression compared to DMSO-treated cells (Table 1).…”

“…33 In addition, tumor cells can be eliminated by NK cells through antibody-dependent cellular cytotoxicity (ADCC) if the proper IgG1 monoclonal antibody (mAb) target is present on the surface of tumor cells. 34–39 We have previously reported the ability of avelumab to mediate the lysis of a range of human carcinomas in vitro by ADCC in the presence of peripheral blood mononuclear cells (PBMCs) or NK cell effectors. 34,39 …”

“…34–39 We have previously reported the ability of avelumab to mediate the lysis of a range of human carcinomas in vitro by ADCC in the presence of peripheral blood mononuclear cells (PBMCs) or NK cell effectors. 34,39 …”

Transcription factors as critical players in melanoma invasiveness, drug resistance, and opportunities for therapeutic drug development

“…Many of the validated GPCRs activate adenyl cyclase, which converts ATP to cAMP, leading to protein kinase A (PKA) activation. Further analysis of the resistance mechanism using melanoma cell lines and patient tumor samples before treatment, during treatment with vemurafenib or dabrafenib/trametinib, and after relapse suggests the hypothesis that cAMP-mediated resistance may operate in part through a CREBdependent mechanism, a downstream effector of cAMP and PKA (Steven & Seliger, 2016). The study also demonstrated that CREB activity was necessary for drug resistance.…”