Differential methylation EPIC analysis discloses cisplatin-resistance related hypermethylation and tumor-specific heterogeneity within matched primary and metastatic testicular germ cell tumor patient tissue samples

Lobo, João; Constâncio, Vera; Leite-Silva, Pedro; Guimarães, Rita; Cantante, Mariana; Braga, Isaac; Maurício, Joaquina; Looijenga, Leendert H. J.; Henrique, Rui; Jerónimo, Carmen

doi:10.1186/s13148-021-01048-y

Cited by 18 publications

(16 citation statements)

References 45 publications

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“…Recent studies suggest that global DNA hypermethylation may be a key factor in mediating cisplatin resistance in TGCTs [16,17]. The current work reveals that DNMT3B is also reciprocally altered with 5-aza and cisplatin resistance.…”

Section: Accepted Articlementioning

confidence: 53%

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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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Section: Accepted Articlementioning

confidence: 53%

“…TGCT patients [17]. Our cisplatin resistant cells also possessed hypomethylation at polycomb target gene promoters, suggesting a complex crosstalk exists between the polycomb and DNA methylation pathways that influences cisplatin sensitivity of TGCT cells [16].…”

Section: Accepted Articlementioning

confidence: 77%

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

et al. 2021

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“…Hypermethylation of the CpG islands of the MLH1 promoter can lead to the accumulation of mismatched nucleotides and the generation of microsatellite instability [59] which have been linked to the poor prognosis of several tumour types but predominantly in colorectal cancers and endometrial cancers [60,61]. Epigenetic silencing of MLH1 is shown to be associated with aggressive tumours and cisplatin resistance in endometrial cancer [62,63] as well as in testicular germ cell tumours [64,65].…”

Section: Mismatch Repair Pathwaymentioning

confidence: 99%

Can Cisplatin Therapy Be Improved? Pathways That Can Be Targeted

Ali

Aouida

Sulaiman

et al. 2022

IJMS

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Cisplatin (cis-diamminedichloroplatinum (II)) is the oldest known chemotherapeutic agent. Since the identification of its anti-tumour activity, it earned a remarkable place as a treatment of choice for several cancer types. It remains effective against testicular, bladder, lung, head and neck, ovarian, and other cancers. Cisplatin treatment triggers different cellular responses. However, it exerts its cytotoxic effects by generating inter-strand and intra-strand crosslinks in DNA. Tumour cells often develop tolerance mechanisms by effectively repairing cisplatin-induced DNA lesions or tolerate the damage by adopting translesion DNA synthesis. Cisplatin-associated nephrotoxicity is also a huge challenge for effective therapy. Several preclinical and clinical studies attempted to understand the major limitations associated with cisplatin therapy, and so far, there is no definitive solution. As such, a more comprehensive molecular and genetic profiling of patients is needed to identify those individuals that can benefit from platinum therapy. Additionally, the treatment regimen can be improved by combining cisplatin with certain molecular targeted therapies to achieve a balance between tumour toxicity and tolerance mechanisms. In this review, we discuss the importance of various biological processes that contribute to the resistance of cisplatin and its derivatives. We aim to highlight the processes that can be modulated to suppress cisplatin resistance and provide an insight into the role of uptake transporters in enhancing drug efficacy.

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“…Another concern that is also related to biomarkers is finding those that can predict response to more targeted (and possibly less toxic) therapies. The epigenetic landscape of TGCTs and its influence also on tumor aggressiveness and response/resistance to cisplatin treatment make epidrugs promising agents [4,13,[22][23][24][25]. In the result of epigenetic targeted therapy studies in TGCTs, other possible biomarkers have been identified, such as LSD1 [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Ki67 and LSD1 Expression in Testicular Germ Cell Tumors Is Not Associated with Patient Outcome: Investigation Using a Digital Pathology Algorithm

Lourenço

Guimarães‐Teixeira

Flores

et al. 2022

Life

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TGCTs represent a model of curable disease afflicting especially young men. Defining tumor biological characteristics is crucial to increase current knowledge and tailor the best clinical management. Ki67, a potential prognostic marker, still exhibits heterogenous associations with patient outcomes, thus bringing the need of corroboration with larger cohorts in clinical practice. LSD1, an epigenetic enzyme, represents a future target for epigenetic drugs that may lower treatment-associated morbidity. This study aimed to assess Ki67/LSD1 immunoexpression across all TGCT histological subtypes and correlate it with clinicopathological features. Results were compared with an in silico analysis of the TCGA database. Immunohistochemistry for Ki67 and LSD1 was carried out in a cohort of 157 TGCT tumor samples and assessed using a digital pathology algorithm. LSD1 protein expression was explored in TGCT cell lines, including ATRA-differentiated clones. There was a significant positive correlation between Ki67 and LSD1 H-scores (rs = 0.182, p = 0.037). Ki67 positivity percentage and H-score were significantly higher in non-seminomas (p = 0.0316 and 0.0113, respectively). Expression was not significantly different according to clinicopathological features, including stage, IGCCCG prognosis-based system, or relapse/progression-free survival, which was corroborated by in silico analysis. Our study, making use of digital image analysis, does not confirm the utility of these biomarkers in a daily practice cohort. Although not affecting patient outcome in our cohort, LSD1 is expressed overall in TGCTs, suggesting sensitivity to LSD1 inhibitors.

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Differential methylation EPIC analysis discloses cisplatin-resistance related hypermethylation and tumor-specific heterogeneity within matched primary and metastatic testicular germ cell tumor patient tissue samples

Cited by 18 publications

References 45 publications

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

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

Can Cisplatin Therapy Be Improved? Pathways That Can Be Targeted

Ki67 and LSD1 Expression in Testicular Germ Cell Tumors Is Not Associated with Patient Outcome: Investigation Using a Digital Pathology Algorithm

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