Transmembrane protein 88 (TMEM88) promoter hypomethylation is associated with platinum resistance in ovarian cancer

Maria de Leon, Horacio Cardenas, Edyta Vieth, Robert Emerson, Matthew Segar, Yunlong Liu, Kenneth Nephew, Daniela Matei

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Objectives: Epigenetic alterations have been implicated in the development of platinum resistance in ovarian cancer (OC). In this study, we aimed to identify DNA methylation changes in platinum resistant tumors and their functional implications. Methods: To identify DNA methylation alterations we used the Illumina 450k DNA methylation array and profiled platinum sensitive and resistant OC xenografts. Validation analyses employed RT-PCR and immunohistochemistry (IHC). Results: Genome-wide DNA methylation analysis of OC xenografts identified 6 genes (SSH3, SLC12A4, TMEM88, PCDHGC3, DAXX, MEST) whose promoters were significantly hypomethylated in resistant compared to sensitive (control) xenografts (p . <. 0.001). We confirmed that . TMEM88 and . DAXX mRNA expression levels were increased in platinum resistant compared to control xenografts, inversely correlated with promoter methylation levels. Furthermore treatment of OC cells with SGI-110 (guadecitabine), a DNA methyl transferase (DNMT) inhibitor, increased . TMEM88 mRNA expression levels, supporting that . TMEM88 is transcriptionally regulated by promoter methylation. TMEM88 was detectable by IHC in all histological types of ovarian tumors and its knock-down by using siRNA promoted OC cell proliferation and colony formation and re-sensitized cells to platinum. Furthermore, . TMEM88 knock down induced upregulation of . cyclin D1 and . c-Myc, known Wnt target genes, supporting that TMEM88 inhibits Wnt signaling. Conclusions: Overall, our results support that OC platinum resistance was correlated with . TMEM88 overexpression regulated through decreased promoter methylation. Our data suggest that . TMEM88 functions as an inhibitor of Wnt signaling, contributing to the development of platinum resistance.

Original languageEnglish (US)
JournalGynecologic Oncology
DOIs
StateAccepted/In press - Mar 23 2016

Fingerprint

Platinum
Ovarian Neoplasms
DNA Methylation
Heterografts
Proteins
Methylation
Member 4 Solute Carrier Family 12
Immunohistochemistry
Messenger RNA
Cyclin D1
Transferases
Oligonucleotide Array Sequence Analysis
Epigenomics
Small Interfering RNA
Genes
Neoplasms
Up-Regulation
Cell Proliferation
Genome
Polymerase Chain Reaction

Keywords

  • Cisplatin resistance
  • DNA methylation
  • Ovarian cancer
  • TMEM88
  • Wnt

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Obstetrics and Gynecology

Cite this

Transmembrane protein 88 (TMEM88) promoter hypomethylation is associated with platinum resistance in ovarian cancer. / de Leon, Maria; Cardenas, Horacio; Vieth, Edyta; Emerson, Robert; Segar, Matthew; Liu, Yunlong; Nephew, Kenneth; Matei, Daniela.

In: Gynecologic Oncology, 23.03.2016.

Research output: Contribution to journalArticle

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abstract = "Objectives: Epigenetic alterations have been implicated in the development of platinum resistance in ovarian cancer (OC). In this study, we aimed to identify DNA methylation changes in platinum resistant tumors and their functional implications. Methods: To identify DNA methylation alterations we used the Illumina 450k DNA methylation array and profiled platinum sensitive and resistant OC xenografts. Validation analyses employed RT-PCR and immunohistochemistry (IHC). Results: Genome-wide DNA methylation analysis of OC xenografts identified 6 genes (SSH3, SLC12A4, TMEM88, PCDHGC3, DAXX, MEST) whose promoters were significantly hypomethylated in resistant compared to sensitive (control) xenografts (p . <. 0.001). We confirmed that . TMEM88 and . DAXX mRNA expression levels were increased in platinum resistant compared to control xenografts, inversely correlated with promoter methylation levels. Furthermore treatment of OC cells with SGI-110 (guadecitabine), a DNA methyl transferase (DNMT) inhibitor, increased . TMEM88 mRNA expression levels, supporting that . TMEM88 is transcriptionally regulated by promoter methylation. TMEM88 was detectable by IHC in all histological types of ovarian tumors and its knock-down by using siRNA promoted OC cell proliferation and colony formation and re-sensitized cells to platinum. Furthermore, . TMEM88 knock down induced upregulation of . cyclin D1 and . c-Myc, known Wnt target genes, supporting that TMEM88 inhibits Wnt signaling. Conclusions: Overall, our results support that OC platinum resistance was correlated with . TMEM88 overexpression regulated through decreased promoter methylation. Our data suggest that . TMEM88 functions as an inhibitor of Wnt signaling, contributing to the development of platinum resistance.",
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AU - de Leon, Maria

AU - Cardenas, Horacio

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AU - Emerson, Robert

AU - Segar, Matthew

AU - Liu, Yunlong

AU - Nephew, Kenneth

AU - Matei, Daniela

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AB - Objectives: Epigenetic alterations have been implicated in the development of platinum resistance in ovarian cancer (OC). In this study, we aimed to identify DNA methylation changes in platinum resistant tumors and their functional implications. Methods: To identify DNA methylation alterations we used the Illumina 450k DNA methylation array and profiled platinum sensitive and resistant OC xenografts. Validation analyses employed RT-PCR and immunohistochemistry (IHC). Results: Genome-wide DNA methylation analysis of OC xenografts identified 6 genes (SSH3, SLC12A4, TMEM88, PCDHGC3, DAXX, MEST) whose promoters were significantly hypomethylated in resistant compared to sensitive (control) xenografts (p . <. 0.001). We confirmed that . TMEM88 and . DAXX mRNA expression levels were increased in platinum resistant compared to control xenografts, inversely correlated with promoter methylation levels. Furthermore treatment of OC cells with SGI-110 (guadecitabine), a DNA methyl transferase (DNMT) inhibitor, increased . TMEM88 mRNA expression levels, supporting that . TMEM88 is transcriptionally regulated by promoter methylation. TMEM88 was detectable by IHC in all histological types of ovarian tumors and its knock-down by using siRNA promoted OC cell proliferation and colony formation and re-sensitized cells to platinum. Furthermore, . TMEM88 knock down induced upregulation of . cyclin D1 and . c-Myc, known Wnt target genes, supporting that TMEM88 inhibits Wnt signaling. Conclusions: Overall, our results support that OC platinum resistance was correlated with . TMEM88 overexpression regulated through decreased promoter methylation. Our data suggest that . TMEM88 functions as an inhibitor of Wnt signaling, contributing to the development of platinum resistance.

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