Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer

Swathi Ramakrishnan, Qiang Hu, Nithya Krishnan, Dan Wang, Evelyn Smit, Victoria Granger, Monika Rak, Kristopher Attwood, Candace Johnson, Carl Morrison, Roberto Pili, Gurkamal Chatta, Khurshid Guru, Geraldine Gueron, Lacey McNally, Jianmin Wang, Anna Woloszynska-Read

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Aberrant DNA methylation observed in cancer can provide survival benefits to cells by silencing genes essential for anti-tumor activity. DNA-demethylating agents such as Decitabine (DAC)/Azacitidine (AZA) activate otherwise silenced tumor suppressor genes, alter immune response and epigenetically reprogram tumor cells. In this study, we show that non-cytotoxic nanomolar DAC concentrations modify the bladder cancer transcriptome to activate NOTCH1 at the mRNA and protein level, increase double-stranded RNA sensors and CK5-dependent differentiation. Importantly, DAC treatment increases ICN1 expression (the active intracellular domain of NOTCH1) significantly inhibiting cell proliferation and causing changes in cell size inducing morphological alterations reminiscent of senescence. These changes were not associated with β-galactosidase activity or increased p16 levels, but instead were associated with substantial IL-6 release. Increased IL-6 release was observed in both DAC-treated and ICN1 overexpressing cells as compared to control cells. Exogenous IL-6 expression was associated with a similar enlarged cell morphology that was rescued by the addition of a monoclonal antibody against IL-6. Treatment with DAC, overexpression with ICN1 or addition of exogenous IL-6 showed CK5 reduction, a surrogate marker of differentiation. Overall this study suggests that in MIBC cells, DNA hypomethylation increases NOTCH1 expression and IL-6 release to induce CK5-related differentiation.

Original languageEnglish (US)
Article number3217
JournalCell Death and Disease
Volume8
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

decitabine
Urinary Bladder Neoplasms
Interleukin-6
Muscles
DNA
Galactosidases
Azacitidine
Neoplasms
Double-Stranded RNA
Essential Genes
Gene Silencing
DNA Methylation
Tumor Suppressor Genes
Cell Size
Transcriptome
Biomarkers
Monoclonal Antibodies
Cell Proliferation

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer. / Ramakrishnan, Swathi; Hu, Qiang; Krishnan, Nithya; Wang, Dan; Smit, Evelyn; Granger, Victoria; Rak, Monika; Attwood, Kristopher; Johnson, Candace; Morrison, Carl; Pili, Roberto; Chatta, Gurkamal; Guru, Khurshid; Gueron, Geraldine; McNally, Lacey; Wang, Jianmin; Woloszynska-Read, Anna.

In: Cell Death and Disease, Vol. 8, No. 12, 3217, 01.12.2017.

Research output: Contribution to journalArticle

Ramakrishnan, S, Hu, Q, Krishnan, N, Wang, D, Smit, E, Granger, V, Rak, M, Attwood, K, Johnson, C, Morrison, C, Pili, R, Chatta, G, Guru, K, Gueron, G, McNally, L, Wang, J & Woloszynska-Read, A 2017, 'Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer', Cell Death and Disease, vol. 8, no. 12, 3217. https://doi.org/10.1038/s41419-017-0024-5
Ramakrishnan, Swathi ; Hu, Qiang ; Krishnan, Nithya ; Wang, Dan ; Smit, Evelyn ; Granger, Victoria ; Rak, Monika ; Attwood, Kristopher ; Johnson, Candace ; Morrison, Carl ; Pili, Roberto ; Chatta, Gurkamal ; Guru, Khurshid ; Gueron, Geraldine ; McNally, Lacey ; Wang, Jianmin ; Woloszynska-Read, Anna. / Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer. In: Cell Death and Disease. 2017 ; Vol. 8, No. 12.
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abstract = "Aberrant DNA methylation observed in cancer can provide survival benefits to cells by silencing genes essential for anti-tumor activity. DNA-demethylating agents such as Decitabine (DAC)/Azacitidine (AZA) activate otherwise silenced tumor suppressor genes, alter immune response and epigenetically reprogram tumor cells. In this study, we show that non-cytotoxic nanomolar DAC concentrations modify the bladder cancer transcriptome to activate NOTCH1 at the mRNA and protein level, increase double-stranded RNA sensors and CK5-dependent differentiation. Importantly, DAC treatment increases ICN1 expression (the active intracellular domain of NOTCH1) significantly inhibiting cell proliferation and causing changes in cell size inducing morphological alterations reminiscent of senescence. These changes were not associated with β-galactosidase activity or increased p16 levels, but instead were associated with substantial IL-6 release. Increased IL-6 release was observed in both DAC-treated and ICN1 overexpressing cells as compared to control cells. Exogenous IL-6 expression was associated with a similar enlarged cell morphology that was rescued by the addition of a monoclonal antibody against IL-6. Treatment with DAC, overexpression with ICN1 or addition of exogenous IL-6 showed CK5 reduction, a surrogate marker of differentiation. Overall this study suggests that in MIBC cells, DNA hypomethylation increases NOTCH1 expression and IL-6 release to induce CK5-related differentiation.",
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AU - Smit, Evelyn

AU - Granger, Victoria

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AU - Johnson, Candace

AU - Morrison, Carl

AU - Pili, Roberto

AU - Chatta, Gurkamal

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AU - Wang, Jianmin

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