Reactivation of endogenous retroviral elements via treatment with DNMT- and HDAC-inhibitors

Michael Daskalakis; David Brocks; Yi-Hua Sheng; Md Saiful Islam; Alzbeta Ressnerova; Yassen Assenov; Till Milde; Ina Oehme; Olaf Witt; Ashish Goyal; Alexander Kühn; Mark Hartmann; Dieter Weichenhan; Manfred Jung; Christoph Plass

doi:10.1080/15384101.2018.1442623

Reactivation of endogenous retroviral elements via treatment with DNMT- and HDAC-inhibitors

Cell Cycle. 2018;17(7):811-822. doi: 10.1080/15384101.2018.1442623. Epub 2018 Apr 30.

Authors

Michael Daskalakis^{1

2}, David Brocks¹, Yi-Hua Sheng³, Md Saiful Islam¹, Alzbeta Ressnerova¹, Yassen Assenov¹, Till Milde^{4

5

6

2}, Ina Oehme^{4

5

6

2}, Olaf Witt^{4

5

6

2}, Ashish Goyal¹, Alexander Kühn¹, Mark Hartmann^{1

7}, Dieter Weichenhan¹, Manfred Jung⁸, Christoph Plass^{1

2}

Affiliations

¹ a Division of Epigenomics and Cancer Risk Factors , German Cancer Research Center , Heidelberg , Germany.
² f German Cancer Research Consortium (DKTK) , Heidelberg , Germany.
³ b School of Pharmacy, College of Medicine , National Taiwan University , Taipei , Taiwan.
⁴ c Translational Program, Hopp Children's Cancer Center at NCT Heidelberg (KiTZ) , Germany.
⁵ d CCU Pediatric Oncology , German Cancer Research Center (DKFZ) , Heidelberg , Germany.
⁶ e Department of Pediatric Oncology, Hematology and Immunology , University Hospital, and Clinical Cooperation Unit Pediatric Oncology, DKFZ , Heidelberg , Germany.
⁷ g Regulation of Cellular Differentiation Group , German Cancer Research Center , Heidelberg , Germany.
⁸ h Institute of Pharmaceutical Sciences, University of Freiburg , Germany.

Abstract

Inhibitors of DNA methyltransferases (DNMTis) or histone deacetylases (HDACis) are epigenetic drugs which are investigated since decades. Several have been approved and are applied in the treatment of hematopoietic and lymphatic malignancies, although their mode of action has not been fully understood. Two recent findings improved mechanistic insights: i) activation of human endogenous retroviral elements (HERVs) with concomitant synthesis of double-stranded RNAs (dsRNAs), and ii) massive activation of promoters from long terminal repeats (LTRs) which originated from past HERV invasions. These dsRNAs activate an antiviral response pathway followed by apoptosis. LTR promoter activation leads to synthesis of non-annotated transcripts potentially encoding novel or cryptic proteins. Here, we discuss the current knowledge of the molecular effects exerted by epigenetic drugs with a focus on DNMTis and HDACis. We highlight the role in LTR activation and provide novel data from both in vitro and in vivo epigenetic drug treatment.

Keywords: Epigenetic therapy; endogenous retroviral elements; viral mimicry.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Antineoplastic Agents / therapeutic use*
Apoptosis / drug effects
Apoptosis / genetics
DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
DNA (Cytosine-5-)-Methyltransferases / genetics*
DNA (Cytosine-5-)-Methyltransferases / metabolism
Endogenous Retroviruses / drug effects*
Endogenous Retroviruses / genetics
Endogenous Retroviruses / metabolism
Enzyme Inhibitors / therapeutic use*
Epigenesis, Genetic*
Gene Expression Regulation, Neoplastic
Hematologic Neoplasms / drug therapy*
Hematologic Neoplasms / enzymology
Hematologic Neoplasms / genetics
Hematologic Neoplasms / pathology
Histone Deacetylase Inhibitors / therapeutic use*
Histone Deacetylases / genetics*
Histone Deacetylases / metabolism
Host-Pathogen Interactions / drug effects
Host-Pathogen Interactions / genetics
Humans
Promoter Regions, Genetic
RNA, Double-Stranded
Terminal Repeat Sequences
Virus Activation / drug effects

Substances

Antineoplastic Agents
Enzyme Inhibitors
Histone Deacetylase Inhibitors
RNA, Double-Stranded
DNA (Cytosine-5-)-Methyltransferases
Histone Deacetylases

Grants and funding

Deutsche Forschungsgemeinschaft [grant numbers SPP1463, FOR2674, W1461/4-1, Oe542/2-1, CRC992]; Deutsche Kinderkrebsstiftung [grant number DKS2009.16]. Funding details: the project was funded in part by DFG Priority Program SPP1463 and FOR 2674, German Cancer Research Consortium (DKTK), German Center for Lung Diseases (DZL). OW (W1461/4-1) and IO (Oe542/2-1) are funded by the Deutsche Forschungsge meinschaft (DFG). Investigator initiated Vorinostat phase I/II trial was supported by a grant from the Deutsche Kinderkrebsstiftung to OW (DKS 2009.16). MJ thanks the DFG (Deutsche Forschungsgemeinschaft, Project A04 within CRC992 Medical Epigenetics) for funding.