Krönung, Sonja Katharina

English

Roughly 8% of the human genome consists of human endogenous retroviruses (HERVs). They are believed to be remnants of ancient retroviral infections of the germline that were passed on from one generation to the next over millions of years. While initially regarded as „junk DNA“, it has become increasingly clear that HERV elements exert defined functions in their hosts. In 2011, our group reported the discovery of an isoform of the tumor suppressor p63 that is expressed under the control of a long terminal repeat (LTR) of the endogenous retrovirus family 9 (termed LTR12). Due to its expression in the spermatogonia of the testis, this isoform was called Germ cell-associated TAp63 (GTAp63). Transcription of GTAp63 was found to be silenced in testicular cancer cells. However, it could be restored by treatment with histone deacetylase inhibitors (HDACi). Moreover, a recent approach identified a set of 17 cellular genes driven by an LTR12 whose transcription can be enhanced by HDACi treatment in testicular cancer cells. Among these genes was TNFRSF10B, which encodes for Death Receptor 5.
Following up on these previous findings, the main goals of this study were to verify TNFRSF10B as a novel candidate gene that is driven by an LTR12, to elucidate the functional implications of this regulation in tumor cells and to clarify the mechanisms behind the localized activation of these specific promoter sites.
We identified at least three LTR12-driven transcripts of TNFRSF10B whose expression is inducible by HDAC inhibitor treatment. Insertion of the solitary LTR12 upstream of the TNFRSF10B gene occurred roughly 18 million years ago. Combined treatment of HDAC inhibitor Trichostatin A (TSA) and TNFRSF10B’s ligand TRAIL resulted in an enhanced apoptotic response in testicular cancer cells. Moreover, we observed enhanced LTR12 promoter activity upon treatment with HDAC inhibitors in a variety of human cancer cell lines. Apart from TSA, induction of LTR12 promoter activity was also observed with the FDA-approved HDAC inhibitor SAHA as well as Entinostat and Mocetinostat, which are currently undergoing phase II clinical trials for cancer therapy. Regarding the mechanisms underlying the specific activation of LTR12-driven gene transcription, we identified increased binding of nuclear transcription factor Y at LTR12 genomic loci upon TSA treatment. The specific activation of LTR12-driven expression of putative tumor suppressor genes like TP63 and TNFRSF10B suggests a novel mechanism of how inhibition of HDACs can exert anti-cancer effects.
Taken together, we present an example of how co-evolution of transposable elements with the host might have been beneficial for the host and therefore be rendered active in the human genome instead of being eliminated as “junk DNA”. Furthermore, LTR12 activation represents a plausible mechanism of how HDAC inhibitors exert anti-cancer activity in human cells

Georg-August-University Göttingen

Role of endogenous retrovirus promoter activity in tumor suppression

https://ediss.uni-goettingen.de/bitstream/11858/00-1735-0000-0022-6008-2/1/PhD_Kroenung_SUB1.pdf

Role of endogenous retrovirus promoter activity in tumor suppression

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Georg-August-University Göttingen