Waddington, C. H. Canalization of development and the inheritance of acquired characters. Nature 150, 563–565 (1942).
Goldberg, A. D., Allis, C. D. & Bernstein, E. Epigenetics: a landscape takes shape. Cell 128, 635–638 (2007).
Brown, R. & Strathdee, G. Epigenomics and epigenetic therapy of cancer. Trends Mol. Med. 8, S43–S48 (2002).
Hoffmann, M. J. & Schulz, W. A. Causes and consequences of DNA hypomethylation in human cancer. Biochem. Cell Biol. 83, 296–321 (2005).
Brown, R., Curry, E., Magnani, L., Wilhelm-Benartzi, C. S. & Borley, J. Poised epigenetic states and acquired drug resistance in cancer. Nat. Rev. Cancer 14, 747–753 (2014).
Esteller, M. & Herman, J. G. Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J. Pathol. 196, 1–7 (2002).
Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012). This is a review summarizing current knowledge on the importance of epigenetic modifications in cancer therapy.
Oosterhuis, J. W. & Looijenga, L. H. J. Testicular germ-cell tumours in a broader perspective. Nat. Rev. Cancer 5, 210–222 (2005). This is a good overview on GCT development in general.
Berney, D. M. et al. Germ cell neoplasia in situ (GCNIS): evolution of the current nomenclature for testicular pre-invasive germ cell malignancy. Histopathology 69, 7–10 (2016).
Spiller, C. M. & Bowles, J. Germ cell neoplasia in situ: the precursor cell for invasive germ cell tumors of the testis. Int. J. Biochem. Cell Biol. 86, 22–25 (2017).
Mitchell, R. T. et al. Intratubular germ cell neoplasia of the human testis: heterogeneous protein expression and relation to invasive potential. Modern Pathol. 27, 1255–1266 (2014).
Kristensen, D. M. et al. Origin of pluripotent germ cell tumours: the role of microenvironment during embryonic development. Mol. Cell. Endocrinol. 288, 111–118 (2008).
Almstrup, K. et al. Carcinoma in situ testis displays permissive chromatin modifications similar to immature foetal germ cells. Br. J. Cancer 103, 1269–1276 (2010).
Eckert, D. et al. TCam-2 but not JKT-1 cells resemble seminoma in cell culture. Cell Tissue Res. 331, 529–538 (2007).
Nettersheim, D. et al. NANOG promoter methylation and expression correlation during normal and malignant human germ cell development. Epigenetics 6, 114–122 (2011).
Kristensen, D. G. et al. Evidence that active demethylation mechanisms maintain the genome of carcinoma in situ cells hypomethylated in the adult testis. Br. J. Cancer 110, 668–678 (2013).
Irie, N. et al. SOX17 is a critical specifier of human primordial germ cell fate. Cell 160, 253–268 (2015).
Hoei-Hansen, C. E. et al. Transcription factor AP-2γ is a developmentally regulated marker of testicular carcinoma in situ and germ cell tumors. Clin. Cancer Res. 10, 8521–8530 (2004).
Meyts, E. R.-D. Developmental expression of POU5F1 (OCT-3/4) in normal and dysgenetic human gonads. Hum. Reprod. 19, 1338–1344 (2004).
Meyts, E. R.-D. & Skakkebaek, N. E. Expression of the c-kit protein product in carcinoma-in-situ and invasive testicular germ cell tumours. Int. J. Androl. 17, 85–92 (1994).
Skakkebæk, N. Possible carcinoma-in-situ of the testis. Lancet 300, 516–517 (1972).
Hoei-Hansen, C. E., Meyts, E. R.-D., Daugaard, G. & Skakkebaek, N. E. Carcinoma in situ testis, the progenitor of testicular germ cell tumours: a clinical review. Ann. Oncol. 16, 863–868 (2005).
Dieckmann, K. P. & Skakkebaek, N. E. Carcinoma in situ of the testis: review of biological and clinical features. Int. J. Cancer 83, 815 (1999).
Hayes-Lattin, B. & Nichols, C. R. Testicular cancer: a prototypic tumor of young adults. Semin. Oncol. 36, 432–438 (2009).
Maso, L. D. et al. Long-term survival, prevalence, and cure of cancer: a population-based estimation for 818 902 Italian patients and 26 cancer types. Ann. Oncol. 25, 2251–2260 (2014).
Albers, P. et al. EAU guidelines on testicular cancer. EAU https://uroweb.org/wp-content/uploads/11-Testicular-Cancer_2017_web.pdf (2017). This is a clinical perspective on current treatment guidelines for testicular GCTs.
Oldenburg, J. et al. Testicular seminoma and non-seminoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 24 (Suppl. 6), 125–132 (2013).
Chovanec, M., Hanna, N., Cary, K. C., Einhorn, L. & Albany, C. Management of stage I testicular germ cell tumours. Nat. Rev. Urol. 13, 663–673 (2016).
Stephenson, A., Khurana, K. & Gilligan, T. Management of poor-prognosis testicular germ cell tumors. Indian J. Urol. 26, 108 (2010).
Oing, C., Seidel, C. & Bokemeyer, C. Therapeutic approaches for refractory germ cell cancer. Expert Rev. Anticancer Ther. 18, 389–397 (2018).
Schmoll, H.-J. et al. Long-term results of first-line sequential high-dose etoposide, ifosfamide, and cisplatin chemotherapy plus autologous stem cell support for patients with advanced metastatic germ cell cancer: an extended phase I/II study of the German Testicular Cancer Study Group. J. Clin. Oncol. 21, 4083–4091 (2003).
Allen, J. C., Kirschner, A., Scarpato, K. R. & Morgans, A. K. Current management of refractory germ cell tumors and future directions. Curr. Oncol. Rep. 19, 8 (2017).
Mayer, F. et al. Molecular determinants of treatment response in human germ cell tumors. Clin. Cancer Res. 9, 767–773 (2003).
Jacobsen, C. & Honecker, F. Cisplatin resistance in germ cell tumours: models and mechanisms. Andrology 3, 111–121 (2014). This is a summary of molecular mechanisms known to provide cisplatin resistance in GCTs.
Galluzzi, L. et al. Molecular mechanisms of cisplatin resistance. Oncogene 31, 1869–1883 (2012).
Honecker, F. et al. Microsatellite instability, mismatch repair deficiency, and BRAF mutation in treatment-resistant germ cell tumors. J. Clin. Oncol. 27, 2129–2136 (2009).
Koster, R. et al. Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer. J. Clin. Invest. 120, 3594–3605 (2010).
Noel, E. E. et al. The association of CCND1 overexpression and cisplatin resistance in testicular germ cell tumors and other cancers. Am. J. Pathol. 176, 2607–2615 (2010).
Koster, R., Timmer-Bosscha, H., Bischoff, R., Gietema, J. A. & de Jong, S. Disruption of the MDM2–p53 interaction strongly potentiates p53-dependent apoptosis in cisplatin-resistant human testicular carcinoma cells via the Fas/FasL pathway. Cell Death Dis. 2, e148 (2011).
Bagrodia, A. et al. Genetic determinants of cisplatin resistance in patients with advanced germ cell tumors. J. Clin. Oncol. 34, 4000–4007 (2016).
Mueller, T. et al. Histological evidence for the existence of germ cell tumor cells showing embryonal carcinoma morphology but lacking OCT4 expression and cisplatin sensitivity. Histochem. Cell Biol. 134, 197–204 (2010).
Mueller, T. et al. Loss of Oct-3/4 expression in embryonal carcinoma cells is associated with induction of cisplatin resistance. Tumor Biol. 27, 71–83 (2006).
Koul, S. et al. Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors. Mol. Cancer 3, 16 (2004).
Talevi, A. Multi-target pharmacology: possibilities and limitations of the ‘skeleton key approach’ from a medicinal chemist perspective. Front. Pharmacol. 6, 205 (2015).
Bhadury, J. et al. BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma. Proc. Natl Acad. Sci. USA 111, E2721–E2730 (2014).
Moore, P. S. et al. Gene expression profiling after treatment with the histone deacetylase inhibitor trichostatin A reveals altered expression of both pro- and anti-apoptotic genes in pancreatic adenocarcinoma cells. Biochim. Biophys. Acta 1693, 167–176 (2004).
da Motta, L. L. et al. The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer. Oncogene 36, 122–132 (2016).
Hoshino, I. et al. Histone demethylase LSD1 inhibitors prevent cell growth by regulating gene expression in esophageal squamous cell carcinoma cells. Ann. Surg. Oncol. 23, 312–320 (2015).
Komashko, V. M. & Farnham, P. J. 5-Azacytidine treatment reorganizes genomic histone modification patterns. Epigenetics 5, 229–240 (2010).
Längst, G. & Manelyte, L. Chromatin remodelers: from function to dysfunction. Genes 6, 299–324 (2015).
Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).
Smiraglia, D. J. et al. Distinct epigenetic phenotypes in seminomatous and nonseminomatous testicular germ cell tumors. Oncogene 21, 3909–3916 (2002).
Wermann, H. et al. Global DNA methylation in fetal human germ cells and germ cell tumours: association with differentiation and cisplatin resistance. J. Pathol. 221, 433–442 (2010).
Shen, H. et al. Integrated molecular characterization of testicular germ cell tumors. Cell Rep. 23, 3392–3406 (2018). This paper provides a detailed molecular characterization of seminoma and non-seminomatous tumours.
Albany, C. et al. Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine. Oncotarget 8, 2949–2959 (2016). This paper describes the second-generation DNA methylation inhibitor SGI-110 and its use for GCT therapy.
Beyrouthy, M. J. et al. High DNA methyltransferase 3B expression mediates 5-Aza-deoxycytidine hypersensitivity in testicular germ cell tumors. Cancer Res. 69, 9360–9366 (2009).
Biswal, B. K. et al. Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-Aza deoxycytidine is associated with global DNA damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLOS ONE 7, e53003 (2012).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT01201811 (2016).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT01074047 (2017).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT01599325 (2018).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT00652626 (2016).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT01751867 (2016).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT01378416 (2011).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT00744757 (2013).
Derissen, E. J. B., Beijnen, J. H. & Schellens, J. H. M. Concise drug review: azacitidine and decitabine. Oncol. 18, 619–624 (2013).
Karahoca, M. & Momparler, R. L. Pharmacokinetic and pharmacodynamic analysis of 5-aza-2′-deoxycytidine (decitabine) in the design of its dose-schedule for cancer therapy. Clin. Epigenet. 5, 3 (2013).
Griffiths, E. A. et al. SGI-110: DNA methyltransferase inhibitor oncolytic. Drugs Future 38, 535–543 (2013).
Issa, J.-P. J. et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet. Oncol. 16, 1099–1110 (2015).
Kantarjian, H. M. et al. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. Lancet. Oncol. 18, 1317–1326 (2017).
Matei, D. et al. A phase I clinical trial of guadecitabine and carboplatin in platinum-resistant, recurrent ovarian cancer: clinical, pharmacokinetic, and pharmacodynamic analyses. Clin. Cancer Res. 24, 2285–2293 (2018).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT02429466 (2018).
Kuang, Y., El-Khoueiry, A., Pietro Taverna, Ljungman, M. & Neamati, N. Guadecitabine (SGI-110) priming sensitizes hepatocellular carcinoma cells to oxaliplatin. Mol. Oncol. 9, 1799–1814 (2015).
Fang, F. et al. The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clin. Cancer Res. 20, 6504–6516 (2014).
Li, Y.-C. et al. Procaine is a specific DNA methylation inhibitor with anti-tumor effect for human gastric cancer. J. Cell. Biochem. 119, 2440–2449 (2018).
Kuck, D., Caulfield, T., Lyko, F. & Medina-Franco, J. L. Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells. Mol. Cancer Ther. 9, 3015–3023 (2010).
Lee, B. H., Yegnasubramanian, S., Lin, X. & Nelson, W. G. Procainamide is a specific inhibitor of DNA methyltransferase 1. J. Biol. Chem. 280, 40749–40756 (2005).
Valente, S. et al. Selective non-nucleoside inhibitors of human DNA methyltransferases active in cancer including in cancer stem cells. J. Med. Chem. 57, 701–713 (2014).
Richardson, B. DNA methylation and autoimmune disease. Clin. Immunol. 109, 72–79 (2003).
Kohli, R. M. & Zhang, Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502, 472–479 (2013).
He, Y.-F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011).
Rasmussen, K. D. & Helin, K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 30, 733–750 (2016). This is a paper on the function of TET enzymes in active DNA demethylation and their implications in cancer development.
Koh, K. P. et al. Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8, 200–213 (2011).
Etchegaray, J.-P. et al. The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine. Nat. Cell Biol. 17, 545–557 (2015).
Nettersheim, D. et al. Analysis of TET expression/activity and 5mC oxidation during normal and malignant germ cell development. PLOS ONE 8, e82881 (2013).
Benešová, M. et al. Overexpression of TET dioxygenases in seminomas associates with low levels of DNA methylation and hydroxymethylation. Mol. Carcinog. 56, 1837–1850 (2017).
Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).
Dang, L., Yen, K. & Attar, E. C. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann. Oncol. 27, 599–608 (2016).
Fu, X., Zhang, P. & Yu, B. Advances toward LSD1 inhibitors for cancer therapy. Future Med. Chem. 9, 1227–1242 (2017).
Alsaqer, S. F. et al. Inhibition of LSD1 epigenetically attenuates oral cancer growth and metastasis. Oncotarget 8, 73372–73386 (2017).
Liang, Y. et al. LSD1-mediated epigenetic reprogramming drives CENPE expression and prostate cancer progression. Cancer Res. 77, 5479–5490 (2017).
Chen, J. et al. Identification of downstream metastasis-associated target genes regulated by LSD1 in colon cancer cells. Oncotarget 8, 19609–19630 (2017).
Przespolewski, A. & Wang, E. S. Inhibitors of LSD1 as a potential therapy for acute myeloid leukemia. Expert Opin. Investig. Drugs 25, 771–780 (2016).
Rudolph, T., Beuch, S. & Reuter, G. Lysine-specific histone demethylase LSD1 and the dynamic control of chromatin. Biol. Chem. 394, 1019–1028 (2013).
Song, Y., Wu, F. & Wu, J. Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives. J. Hematol. Oncol. 9, 49 (2016).
Zheng, Y. C. et al. Irreversible LSD1 inhibitors: application of tranylcypromine and its derivatives in cancer treatment. Curr. Top. Med. Chem. 16, 2179–2188 (2016).
Duan, Y.-C. et al. Design and synthesis of tranylcypromine derivatives as novel LSD1/HDACs dual inhibitors for cancer treatment. Eur. J. Med. Chem. 140, 392–402 (2017).
Civenni, G. et al. INCB059872, a novel FAD-directed LSD1 inhibitor, is active in prostate cancer models and impacts prostate cancer stem-like cells. Cancer Res. 78, 1379–1379 (2018).
Moreno, V. et al. A phase I, open-label, study of GSK2879552, a lysine-specific demethylase 1 (LSD1) inhibitor, in patients with relapsed/refractory small cell lung carcinoma (SCLC). Ann. Oncol. 27, 381P (2016).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT01430455 (2018).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT03136185 (2018).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT03514407 (2018).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT02929498 (2017).
Wang, J. et al. Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Res. 71, 7238–7249 (2011).
Hoang, N. et al. New histone demethylase LSD1 inhibitor selectively targets teratocarcinoma and embryonic carcinoma cells. Bioorg. Med. Chem. 26, 1523–1537 (2018). This is an exemplary publication on the development and functional validation of LSD1 inhibitors for GCT therapy.
Yin, F. et al. LSD1 regulates pluripotency of embryonic stem/carcinoma cells through histone deacetylase 1-mediated deacetylation of histone H4 at lysine 16. Mol. Cell. Biol. 34, 158–179 (2014).
Qureshi, I. A., Gokhan, S. & Mehler, M. F. REST and CoREST are transcriptional and epigenetic regulators of seminal neural fate decisions. Cell Cycle 9, 4477–4486 (2010).
Kalin, J. H. et al. Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors. Nat. Commun. 9, 53 (2018). This publication describes the development of the hybrid inhibitor corin and its efficacy in a multitarget pharmacology approach.
Nettersheim, D., Gillis, A., Biermann, K., Looijenga, L. H. J. & Schorle, H. The seminoma cell line TCam-2 is sensitive to HDAC inhibitor depsipeptide but tolerates various other chemotherapeutic drugs and loss of NANOG expression. Genes Chromosomes Cancer 50, 1033–1042 (2011).
Zhang, T., Cooper, S. & Brockdorff, N. The interplay of histone modifications — writers that read. EMBO Rep. 16, 1467–1481 (2015).
Eberharter, A. & Becker, P. B. Histone acetylation: a switch between repressive and permissive chromatin: Second in review series on chromatin dynamics. EMBO Rep. 3, 224–229 (2002).
Bannister, A. J. & Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res. 21, 381–395 (2011).
Seto, E. & Yoshida, M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 6, a018713 (2014).
Nettersheim, D. et al. A signaling cascade including ARID1A, GADD45B and DUSP1 induces apoptosis and affects the cell cycle of germ cell cancers after romidepsin treatment. Oncotarget 7, 74931–74946 (2016). This paper provides a detailed description on the molecular pathways mediating the romidepsin response in GCT models.
Marks, P. A. & Breslow, R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat. Biotechnol. 25, 84–90 (2007).
Foss, F. et al. Romidepsin for the treatment of relapsed/refractory peripheral T cell lymphoma: prolonged stable disease provides clinical benefits for patients in the pivotal trial. J. Hematol. Oncol. 9, 22 (2016).
Dong, M. et al. Phase I study of chidamide (CS055/HBI-8000), a new histone deacetylase inhibitor, in patients with advanced solid tumors and lymphomas. Cancer Chemother. Pharmacol. 69, 1413–1422 (2012).
Kirschbaum, M. H. et al. A phase 2 study of belinostat (PXD101) in patients with relapsed or refractory acute myeloid leukemia or patients over the age of 60 with newly diagnosed acute myeloid leukemia: a California Cancer Consortium Study. Leuk. Lymphoma 55, 2301–2304 (2014).
Yee, A. J. & Raje, N. S. Panobinostat and multiple myeloma in 2018. Oncologist 23, 516–517 (2018).
Lech-Maranda, E., Robak, E., Korycka, A. & Robak, T. Depsipeptide (FK228) as a novel histone deacetylase inhibitor: mechanism of action and anticancer activity. Mini Rev. Med. Chem. 7, 1062–1069 (2007).
Radzisheuskaya, A. et al. A defined Oct4 level governs cell state transitions of pluripotency entry and differentiation into all embryonic lineages. Nat. Cell Biol. 15, 579–590 (2013).
You, J. S. et al. Depletion of embryonic stem cell signature by histone deacetylase inhibitor in NCCIT cells: involvement of Nanog suppression. Cancer Res. 69, 5716–5725 (2009).
Furumai, R. et al. FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res. 69, 5716–5725 (2002).
Lauffer, B. E. L. et al. Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability. J. Biol. Chem. 288, 26926–26943 (2013).
Damjanov, I., Horvat, B. & Gibas, Z. Retinoic acid-induced differentiation of the developmentally pluripotent human germ cell tumor-derived cell line, NCCIT. Lab. Invest. 68, 220–232 (1993).
Moasser, M. M. et al. All-trans retinoic acid for treating germ cell tumors. In vitro activity and results of a phase II trial. Cancer 76, 680–686 (1995).
Mei, D. et al. All-trans retinoic acid suppresses malignant characteristics of CD133-positive thyroid cancer stem cells and induces apoptosis. PLOS ONE 12, e0182835 (2017).
Nguyen, P. H. et al. All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth. Oncogene 35, 5619–5628 (2016).
Yan, Y. et al. All-trans retinoic acids induce differentiation and sensitize a radioresistant breast cancer cells to chemotherapy. BMC Complement. Altern. Med. 16, 113 (2016).
Minucci, S. et al. A histone deacetylase inhibitor potentiates retinoid receptor action in embryonal carcinoma cells. Proc. Natl Acad. Sci. USA 94, 11295–11300 (1997).
Yang-Yen, H. F., Chiu, R. & Karin, M. Elevation of AP1 activity during F9 cell differentiation is due to increased c-jun transcription. New Biol. 2, 351–361 (1990).
de Groot, R. P., Schoorlemmer, J., van Ganesen, S. T. & Kruijer, W. Differential expression of jun and fos genes during differentiation of mouse P19 embryonal carcinoma cells. Nucleic Acids Res. 18, 3195–3202 (1990).
Jin, C. et al. JDP2, a repressor of AP-1, recruits a histone deacetylase 3 complex to inhibit the retinoic acid-induced differentiation of F9 cells. Mol. Cell. Biol. 22, 4815–4826 (2002).
Curtin, J. C. & Spinella, M. J. p53 in human embryonal carcinoma: identification of a transferable, transcriptional repression domain in the N-terminal region of p53. Oncogene 24, 1481–1490 (2005).
Curtin, J. C. et al. Retinoic acid activates p53 in human embryonal carcinoma through retinoid receptor-dependent stimulation of p53 transactivation function. Oncogene 20, 2559–2569 (2001).
Voutsadakis, I. A. The chemosensitivity of testicular germ cell tumors. Cell. Oncol. 37, 79–94 (2014).
Arts, J. et al. JNJ-26481585, a novel ‘second-generation’ oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity. Clin. Cancer Res. 15, 6841–6851 (2009).
Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010).
Matzuk, M. M. et al. Small-molecule inhibition of BRDT for male contraception. Cell 150, 673–684 (2012).
Muller, S., Filippakopoulos, P. & Knapp, S. Bromodomains as therapeutic targets. Expert Rev. Mol. Med. 13, 265 (2011). This review highlights the importance of bromodomain readers as targets for cancer therapy.
Taniguchi, Y. The bromodomain and extra-terminal domain (BET) family: functional anatomy of BET paralogous proteins. Int. J. Mol. Sci. 17, E1849 (2016).
Nicodeme, E. et al. Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119–1123 (2010).
Beesley, A. H. et al. Comparative drug screening in NUT midline carcinoma. Br. J. Cancer 110, 1189–1198 (2014).
Asangani, I. A. et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510, 287–282 (2014).
Cheng, Z. et al. Inhibition of BET bromodomain targets genetically diverse glioblastoma. Clin. Cancer Res. 19, 1748–1759 (2013).
Feng, Q. et al. An epigenomic approach to therapy for tamoxifen-resistant breast cancer. Cell Res. 19, 1748–1759 (2014).
Delmore, J. E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011).
Baker, E. K. et al. BET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells. Sci. Rep. 5, 10120 (2015).
Lockwood, W. W., Zejnullahu, K., Bradner, J. E. & Varmus, H. Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proc. Natl Acad. Sci. USA 109, 19408–19413 (2012).
Henssen, A. G. et al. BET bromodomain protein inhibition is a therapeutic option for medulloblastoma. Oncotarget 4, 2080–2095 (2013).
Chung, C. & Mirguet, O. Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J. Med. Chem. 56, 7501–7515 (2013).
Faivre, E. J. et al. Exploitation of castration-resistant prostate cancer transcription factor dependencies by the novel BET inhibitor ABBV-075. Mol. Cancer Res. 15, 35–44 (2016).
Bernasconi, E. et al. Preclinical evaluation of the BET bromodomain inhibitor BAY 1238097 for the treatment of lymphoma. Br. J. Haematol. 178, 936–948 (2017).
Gerlach, D. et al. The novel BET bromodomain inhibitor BI 894999 represses super-enhancer-associated transcription and synergizes with CDK9 inhibition in AML. Oncogene 37, 2687–2701 (2018).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT02391480 (2018).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT02516553 (2019).
Doroshow, D. B., Eder, J. P. & LoRusso, P. M. BET inhibitors: a novel epigenetic approach. Ann. Oncol. 28, 1776–1787 (2017).
Jostes, S. et al. The bromodomain inhibitor JQ1 triggers growth arrest and apoptosis in testicular germ cell tumours in vitro and in vivo. J. Cell. Mol. Med. 21, 1300–1314 (2017). This paper describes the effects of BET inhibition in GCT models.
Nettersheim, D. et al. BMP inhibition in seminomas initiates acquisition of pluripotency via NODAL signaling resulting in reprogramming to an embryonal carcinoma. PLOS Genet. 11, e1005415 (2015).
Mazur, P. K. et al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat. Med. 21, 1163–1171 (2015).
Borbely, G., Haldosen, L.-A., Dahlman-Wright, K. & Zhao, C. Induction of USP17 by combining BET and HDAC inhibitors in breast cancer cells. Oncotarget 6, 33623–33635 (2015).
Adeegbe, D. O. et al. Synergistic immunostimulatory effects and therapeutic benefit of combined histone deacetylase and bromodomain inhibition in non–small cell lung cancer. Cancer Discov. 7, 852–867 (2017).
Gendarme, M., Baumann, J., Ignashkova, T. I., Lindemann, R. K. & Reiling, J. H. Image-based drug screen identifies HDAC inhibitors as novel Golgi disruptors synergizing with JQ1. Mol. Biol. Cell 28, 3756–3772 (2017).
Shang, E., Nickerson, H. D., Wen, D., Wang, X. & Wolgemuth, D. J. The first bromodomain of Brdt, a testis-specific member of the BET sub-family of double-bromodomain-containing proteins, is essential for male germ cell differentiation. Development 134, 3507–3515 (2007).
Pivot-Pajot, C. et al. Acetylation-dependent chromatin reorganization by BRDT, a testis-specific bromodomain-containing protein. Mol. Cell. Biol. 23, 5354–5365 (2003).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT01713582 (2018).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT02698189 (2018).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT02259114 (2018).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT02698176 (2018).
US National Library of Medicine. ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT02296476 (2018).
Odore, E. et al. Phase I population pharmacokinetic assessment of the oral bromodomain inhibitor OTX015 in patients with haematologic malignancies. Clin. Pharmacokinet. 55, 397–405 (2015).
Zengerle, M., Chan, K.-H. & Ciulli, A. Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol. 10, 1770–1777 (2015). This paper presents an alternative strategy to BET inhibition using PROTACs in order to selectively ubiquitylate the BET target proteins, resulting in degradation.
Bondeson, D. P. et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol. 25, 78–87 (2018).
Hasan, S. & Hottiger, M. O. Histone acetyl transferases: a role in DNA repair and DNA replication. J. Mol. Med. 80, 463–474 (2002).
Li, Y. & Seto, E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb. Perspect. Med. 6, a026831 (2016).
Honorio, S. et al. Frequent epigenetic inactivation of the RASSF1A tumour suppressor gene in testicular tumours and distinct methylation profiles of seminoma and nonseminoma testicular germ cell tumours. Oncogene 22, 461–466 (2003).
Cheung, H.-H., Yang, Y., Lee, T.-L., Rennert, O. & Chan, W.-Y. Hypermethylation of genes in testicular embryonal carcinomas. Br. J. Cancer 114, 230–236 (2016).
Christoph, F. et al. Frequent epigenetic inactivation of p53 target genes in seminomatous and nonseminomatous germ cell tumors. Cancer Lett. 247, 137–142 (2007).
Brait, M. et al. DNA methylation profiles delineate epigenetic heterogeneity in seminoma and non-seminoma. Br. J. Cancer 106, 414–423 (2012).
Ellinger, J. et al. CpG island hypermethylation of cell-free circulating serum DNA in patients with testicular cancer. J. Urol. 182, 324–329 (2009).
Cheung, H. H. et al. Genome-wide DNA methylation profiling reveals novel epigenetically regulated genes and non-coding RNAs in human testicular cancer. Br. J. Cancer 102, 419–427 (2010).
Chaubert, P. et al. Frequent p161NK4 (MTS1) gene inactivation in testicular germ cell tumors. J. Urol. 159, 2240 (1998).
Spiller, C. M. et al. Cripto: expression, epigenetic regulation and potential diagnostic use in testicular germ cell tumors. Mol. Oncol. 10, 526–537 (2016).
Sievers, S. et al. IGF2/H19 imprinting analysis of human germ cell tumors (GCTs) using the methylation-sensitive single-nucleotide primer extension method reflects the origin of GCTs in different stages of primordial germ cell development. Genes Chromosomes Cancer 44, 256–264 (2005).
Chen, B.-F., Suen, Y.-K., Gu, S., Li, L. & Chan, W.-Y. A. miR-199a/miR-214 self-regulatory network via PSMD10, TP53 and DNMT1 in testicular germ cell tumor. Sci. Rep. 4, 6413 (2014).
De Jong, J., Weeda, S., Gillis, A. J. M., Oosterhuis, J. W. & Looijenga, L. H. J. Differential methylation of the OCT3/4 upstream region in primary human testicular germ cell tumors. Oncol. Rep. 18, 127–132 (2007).