Hypermethylation and global remodelling of DNA methylation is associated with acquired cisplatin resistance in testicular germ cell tumours

Fazal, Zeeshan; Singh, Ratnakar; Fang, Fang; Bikorimana, Emmanuel; Baldwin, Hannah; Corbet, Andrea; Tomlin, Megan; Yerby, Cliff; Adra, Nabil; Albany, Costantine; Lee, Sarah; Freemantle, Sarah J.; Nephew, Kenneth P.; Christensen, Brock C.; Spinella, Michael J.

doi:10.1080/15592294.2020.1834926

Cited by 25 publications

(40 citation statements)

References 47 publications

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“…DNA methylation has been recognized as an important mechanism during TGCT progression and chemosensitivity [ 113 , 114 , 115 , 116 ]. TGCT genomic DNA is hypomethylated in comparison to most solid tumors.…”

Section: Epigenetic States In Testicular Germ Cell Tumors Associatmentioning

confidence: 99%

“…There is evidence to suggest that hypermethylation of TGCTs especially EC and other nonseminoma subtypes may be associated with cisplatin resistance. Several specific gene promoters and differentially methylated regions (DMRs) have been associated with inherent and acquired cisplatin resistance in TGCTs and cell lines including RASSF1A , HIC1 , MGMT , and CALCA [ 113 , 114 , 115 , 116 ]. Additionally, cisplatin treatment has been shown to be associated with increased DNA methylation in vivo [ 114 ].…”

Section: Epigenetic States In Testicular Germ Cell Tumors Associatmentioning

confidence: 99%

“…Utilizing a series of isogenic cisplatin-resistant cell models we demonstrated a strong association between cisplatin resistance in TGCT cells and a net increase in global CpG and non-CpG DNA methylation spanning regulatory, intergenic, genic, and repeat elements [ 113 ]. Integrative transcriptome and methylome analyses revealed a strong negative correlation between gene promoter and CpG island methylation and gene expression in resistant cells.…”

Section: Epigenetic States In Testicular Germ Cell Tumors Associatmentioning

confidence: 99%

“…Integrative transcriptome and methylome analyses revealed a strong negative correlation between gene promoter and CpG island methylation and gene expression in resistant cells. A bidirectional shift between gene promoter and gene body DNA methylation occurred within multiple genes that was associated with upregulation of polycomb targets and downregulation of tumor suppressor genes [ 113 ]. These findings suggest that global remodeling of DNA methylation is a key factor in mediating cisplatin hypersensitivity and that chemoresistance of TGCTs is mediated by a complex interplay between DNA methylation and the polycomb pathway (see below) [ 113 ].…”

Section: Epigenetic States In Testicular Germ Cell Tumors Associatmentioning

confidence: 99%

“…Importantly, repression of H3K27 methylation with the EZH2 inhibitor GSK126 conferred cisplatin resistance to parental cells while induction of H3K27 methylation with the histone lysine demethylase inhibitor GSKJ4 resulted in increased cisplatin sensitivity to resistant cells, suggesting that the polycomb pathway is involved in the regulation of cisplatin sensitivity of TGCT cells [ 139 ]. As stated above, follow up analysis of these cisplatin resistant models suggest the same polycomb target genes are coordinately regulated by both H3K27 methylation and DNA methylation [ 113 ]. In summary, studies on epigenetic targeting of TGCTs suggest that tumorigenicity in this pluripotent, germ cell context may be especially vulnerable to epigenetic alterations compared to somatic cancers.…”

Section: Epigenetic States In Testicular Germ Cell Tumors Associatmentioning

confidence: 99%

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Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

Singh

Fazal

Freemantle

et al. 2021

Cancers

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Compared to many common solid tumors, the main genetic drivers of most testicular germ cell tumors (TGCTs) are unknown. Decades of focus on genomic alterations in TGCTs including awareness of a near universal increase in copies of chromosome 12p have failed to uncover exceptional driver genes, especially in genes that can be targeted therapeutically. Thus far, TGCT patients have missed out on the benefits of targeted therapies available to treat most other malignancies. In the past decade there has been a greater appreciation that epigenetics may play an especially prominent role in TGCT etiology, progression, and hypersensitivity to conventional chemotherapy. While genetics undoubtedly plays a role in TGCT biology, this mini-review will focus on the epigenetic “states” or features of testicular cancer, with an emphasis on DNA methylation, histone modifications, and miRNAs associated with TGCT susceptibility, initiation, progression, and response to chemotherapy. In addition, we comment on the current status of epigenetic-based therapy and epigenetic biomarker development for TGCTs. Finally, we suggest a unifying “rock and a hard place” or “differentiate or die” model where the tumorigenicity and curability of TGCTs are both dependent on common but still ill-defined epigenetic states.

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Section: Epigenetic States In Testicular Germ Cell Tumors Associatmentioning

confidence: 99%

Section: Epigenetic States In Testicular Germ Cell Tumors Associatmentioning

confidence: 99%

Section: Epigenetic States In Testicular Germ Cell Tumors Associatmentioning

confidence: 99%

Section: Epigenetic States In Testicular Germ Cell Tumors Associatmentioning

confidence: 99%

Section: Epigenetic States In Testicular Germ Cell Tumors Associatmentioning

confidence: 99%

See 3 more Smart Citations

Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

Singh

Fazal

Freemantle

et al. 2021

Cancers

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Reciprocal epigenetic remodeling controls testicular cancer hypersensitivity to hypomethylating agents and chemotherapy

et al. 2021

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Testicular germ cell tumors (TGCTs) are aggressive but sensitive to cisplatin-based chemotherapy.Alternative therapies are needed for tumors refractory to cisplatin with hypomethylating agents providing one possibility. The mechanisms of cisplatin hypersensitivity and resistance in TGCTs remain poorly understood. Recently, it has been shown that TGCTs, even those resistant to cisplatin, are hypersensitive to very low doses of hypomethylating agents including 5-aza deoxy-cytosine (5aza) and guadecitabine. We undertook a pharmacogenomic approach in order to better understand mechanisms of TGCT hypomethylating agent hypersensitivity by generating a panel of acquired 5aza resistant TGCT cells and contrasting these to previously generated acquired isogenic cisplatin resistant cells from the same parent. Interestingly, there was a reciprocal relationship between cisplatin and 5-aza sensitivity, with cisplatin resistance associated with increased sensitivity to 5-aza and 5-aza resistance associated with increased sensitivity to cisplatin. Unbiased transcriptome analysis revealed 5-aza resistant cells strongly downregulated polycomb target gene expression, the exact opposite of the finding for cisplatin resistant cells which upregulated polycomb target genes.This was associated with a dramatic increase in H3K27me3 and decrease in DNMT3B levels in 5aza resistant cells, the exact opposite changes seen in cisplatin resistant cells. Evidence is presented that reciprocal regulation of polycomb and DNMT3B may be initiated by changes in DNMT3B levels as DNMT3B knockdown alone in parental cells resulted in increased expression of H3K27me3, EZH2 and BMI1, conferred 5-aza resistance and cisplatin sensitization, and mediated genome-wide repression of polycomb target gene expression. Finally, genome-wide analysis revealed that 5-aza resistant, cisplatin resistant and DNMT3B knockdown cells alter the expression of a common set of polycomb target genes. This study highlights that reciprocal epigenetic changes mediated by DNMT3B and polycomb may be a key driver of the unique cisplatin and 5-aza hypersensitivity of TGCTs and suggests that distinct epigenetic vulnerabilities may exist for pharmacological targeting of TGCTs.

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Glycan signatures for the identification of cisplatin‐resistant testicular cancer cell lines: Specific glycoprofiling of human chorionic gonadotropin (hCG)

et al. 2022

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Background Testicular cancer (TC) is the most frequent type of cancer among young men aged between 15 and 34 years. TC is treated using cisplatin, but 3%–5% of TC patients fail to respond to cisplatin, with a very bad to fatal prognosis. Accordingly, it is most important to quickly and readily identify those TC patients who are resistant to cisplatin treatment. Methods This study seeks to investigate changes in the glycosylation associated with cisplatin resistance to TC cell lines. Results A specific glycoprofiling of human chorionic gonadotropin (hCG) was analysed in three TC cell lines and one cell line of female origin. A typical calibration curve for hCG glycoprofiling showed a dynamic range up to 50 ng/ml, with a limit of detection of 0.3 ng/ml and assay reproducibility represented by relative standard deviation of 3.0%. Changes in the glycan signatures on hCG were analysed in cisplatin‐sensitive cell lines and in their cisplatin‐resistant sub‐lines using an enzyme‐linked lectin assay (ELLA) protocol. An immobilised antibody was applied to a selective capture of hCG from a cytoplasmic fraction of cell lysates with final incubation using a lectin from a panel of 17 lectins. Conclusion The results suggest that one particular lectin Dolichos biflorus agglutinin (DBA) can selectively discriminate sensitive TC cell lines from resistant TC cell lines. Moreover, there are additional lectins which can provide useful information about the strength of cisplatin resistance.

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Hypermethylation and global remodelling of DNA methylation is associated with acquired cisplatin resistance in testicular germ cell tumours

Cited by 25 publications

References 47 publications

Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

Reciprocal epigenetic remodeling controls testicular cancer hypersensitivity to hypomethylating agents and chemotherapy

Glycan signatures for the identification of cisplatin‐resistant testicular cancer cell lines: Specific glycoprofiling of human chorionic gonadotropin (hCG)

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