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Epigenetic drugs and their molecular targets in testicular germ cell tumours

Nature Reviews Urology volume 16, pages 245–259 (2019)Cite this article

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Abstract

Current treatment regimens for type II testicular germ cell tumours (TGCTs) achieve cure rates of ≥95%; however, 1–5% of TGCTs develop resistance to standard platinum-based chemotherapy. Patients with recurrent TGCT typically receive high-dose chemotherapy, but this treatment results in severe adverse effects and cytotoxicity. Thus, alternative treatment options should be considered to improve patient well-being and quality of life. Epigenetic drugs could be feasible options for TGCT treatment. Several compounds have already been tested in TGCT cell lines and xenograft models with promising results. These compounds include DNA demethylating agents (such as SGI-110), histone demethylase inhibitors (such as the lysine-specific histone demethylase 1A (LSD1) inhibitor CBB3001), histone deacetylase (HDAC) inhibitors (such as romidepsin) and bromodomain inhibitors (such as JQ1). Despite the diversity in their molecular effects, most epigenetic compounds show strong overlap in their genetic response. The use of epigenetic drugs in TGCTs triggers a cellular stress response, induction of differentiation and downregulation of genes associated with pluripotency, leading to growth arrest and apoptosis. Additive effects are seen using a combination of JQ1 and romidepsin. The availability of dual drugs (such as LSD1–HDAC1 hybrid inhibitors) could additionally take advantage of drug synergy effects. Thus, epigenetic drugs are novel tools that could be combined with standard therapy approaches to improve treatment of TGCTs.

Key points

  • Overall, 1–5% of testicular germ cell tumours (TGCTs) are resistant to standard therapy regimens. However, TGCTs harbour epigenetic alterations, which can be targeted by specific therapeutic approaches.

  • Re-expression of tumour suppressor genes by DNA demethylating agents might resensitize refractory embryonal carcinomas to chemotherapy.

  • Embryonal carcinomas are particularly sensitive to lysine-specific histone demethylase 1A (LSD1) inhibitor treatment, as they have higher LSD1 levels than somatic tumours.

  • Histone deacetylase 1 (HDAC1) was identified as a primary target for TGCT therapy among different HDAC proteins. The HDAC1 inhibitor romidepsin leads to apoptosis, cell cycle arrest and downregulation of pluripotency in TGCTs.

  • Owing to its high bioavailability in testes and brain, the small molecule JQ1 seems ideally suited for targeting germ cell tumours. Bromodomain and extraterminal domain (BET) protein inhibition potently induces apoptosis and cell cycle arrest, especially in non-seminomas.

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Fig. 1: The writers, readers and erasers of epigenetic modifications in TGCT development.
Fig. 2: DNA methylation in TGCTs.
Fig. 3: DNA demethylation in TGCTs.
Fig. 4: Histone demethylation in TGCTs.
Fig. 5: Histone deacetylation in TGCTs.
Fig. 6: Bromodomains in TGCTs.

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Acknowledgements

The authors acknowledge grant support from the German Research Foundation (DFG) and the Sander-Stiftung.

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Nature Reviews Urology thanks A. Bagrodia and M. Murray for their contribution to the peer review of this work.

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Author notes

  1. These authors contributed equally: Daniel Nettersheim, Hubert Schorle.

Authors and Affiliations

  1. Institute of Pathology, Department of Developmental Pathology, University of Bonn Medical School, Bonn, Germany

    Sina Jostes & Hubert Schorle

  2. Department of Urology, Urological Research Lab, Translational Urooncology, University Medical School Düsseldorf, Düsseldorf, Germany

    Daniel Nettersheim

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S.J. researched data and wrote the manuscript; all authors made substantial contributions to discussion of content and reviewed and edited the article before submission.

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Glossary

Epigenetics

Changes in gene expression that are independent of the underlying DNA sequence.

Histone deacetylases

Enzymes involved in deacetylation of histones, thereby modulating chromatin structure.

Testicular germ cell tumours

(TGCTs). A heterogeneous group of testicular neoplasms originating from male germ cells.

Germ cell neoplasia in situ

(GCNIS). An asymptomatic precursor lesion of testicular germ cell tumours that is believed to be already present at birth.

Primordial germ cells

(PGCs). Primary undifferentiated germ cells that will differentiate into sperm or oocytes.

TNM(S) classification

A staging system of testicular germ cell tumours according to size of the tumour (T), the number of infiltrated lymph nodes (N), the number of metastases (M) and blood serum markers (S).

Cisplatin

A common type of platinum-based chemotherapy, which causes DNA damage and results in apoptosis of tumour cells.

Bromodomain and extraterminal domain

(BET). Epigenetic readers that regulate gene transcription by recruiting different molecular partner proteins to acetylated histones.

Nucleoside analogue

A drug type that can be used as an inhibitor of DNA methylation, such as the cytidine analogues 5-azacytidine (5-aza-C) and 5-azacytidine-2′deoxycytidine (5-aza-CdR), as it will incorporate into the DNA but cannot be methylated.

Ten-eleven translocation (TET) enzymes

Enzymes that oxidize 5-methylcytosine to 5-hydroxymethylcytosine and then 5-formylcytosine, thereby promoting reversal of DNA methylation.

CoREST complex

A protein complex comprising histone deacetylase 1 (HDAC1), REST co-repressor 1 (CoREST) and lysine-specific histone demethylase 1A (LSD1) that functions as a transcriptional repressor or activator.

Proteolysis targeted chimaera

(PROTAC). A drug composed of an E3 ubiquitin ligase fused to a second compound that binds the target protein. This results in recruitment of the E3 ligase to the target protein to mark it for proteasomal degradation.

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Jostes, S., Nettersheim, D. & Schorle, H. Epigenetic drugs and their molecular targets in testicular germ cell tumours. Nat Rev Urol 16, 245–259 (2019). https://doi.org/10.1038/s41585-019-0154-x

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