DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine

Jia Yu, Bo Qin, Ann Moyer, Somaira Nowsheen, Tongzheng Liu, Sisi Qin, Yongxian Zhuang, Duan Liu, Shijia W. Lu, Krishna R Kalari, Daniel W Visscher, John A III Copland, Sarah A. McLaughlin, Alvaro Moreno Aspitia, Donald W Northfelt, Richard J. Gray, Zhenkun Lou, Vera Jean Suman, Richard M Weinshilboum, Judy C BougheyMatthew Philip Goetz, Liewei M Wang

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis that lacks targeted therapies, especially in patients with chemotherapy-resistant disease. Since DNA methylation-induced silencing of tumor suppressors is common in cancer, reversal of promoter DNA hypermethylation by 5-aza-2'-deoxycytidine (decitabine), an FDA-approved DNA methyltransferase (DNMT) inhibitor, has proven effective in treating hematological neoplasms. However, its antitumor effect varies in solid tumors, stressing the importance of identifying biomarkers predictive of therapeutic response. Here, we focused on the identification of biomarkers to select decitabine-sensitive TNBC through increasing our understanding of the mechanism of decitabine action. We showed that protein levels of DNMTs correlated with response to decitabine in patient-derived xenograft (PDX) organoids originating from chemotherapy-sensitive and -resistant TNBCs, suggesting DNMT levels as potential biomarkers of response. Furthermore, all 3 methytransferases, DNMT1, DNMT3A, and DNMT3B, were degraded following low-concentration, long-term decitabine treatment both in vitro and in vivo. The DNMT proteins could be ubiquitinated by the E3 ligase, TNF receptor-associated factor 6 (TRAF6), leading to lysosome-dependent protein degradation. Depletion of TRAF6 blocked decitabine-induced DNMT degradation, conferring resistance to decitabine. Our study suggests a potential mechanism of regulating DNMT protein degradation and DNMT levels as response biomarkers for DNMT inhibitors in TNBCs.

Original languageEnglish (US)
Pages (from-to)2376-2388
Number of pages13
JournalJournal of Clinical Investigation
Volume128
Issue number6
DOIs
StatePublished - Jun 1 2018

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decitabine
Triple Negative Breast Neoplasms
Methyltransferases
DNA
Biomarkers
TNF Receptor-Associated Factor 6
Proteolysis
Protein Methyltransferases
Organoids
Drug Therapy
Neoplasms
Ubiquitin-Protein Ligases
Hematologic Neoplasms
DNA Methylation
Lysosomes
Heterografts

ASJC Scopus subject areas

  • Medicine(all)

Cite this

DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine. / Yu, Jia; Qin, Bo; Moyer, Ann; Nowsheen, Somaira; Liu, Tongzheng; Qin, Sisi; Zhuang, Yongxian; Liu, Duan; Lu, Shijia W.; Kalari, Krishna R; Visscher, Daniel W; Copland, John A III; McLaughlin, Sarah A.; Moreno Aspitia, Alvaro; Northfelt, Donald W; Gray, Richard J.; Lou, Zhenkun; Suman, Vera Jean; Weinshilboum, Richard M; Boughey, Judy C; Goetz, Matthew Philip; Wang, Liewei M.

In: Journal of Clinical Investigation, Vol. 128, No. 6, 01.06.2018, p. 2376-2388.

Research output: Contribution to journalArticle

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title = "DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine",
abstract = "Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis that lacks targeted therapies, especially in patients with chemotherapy-resistant disease. Since DNA methylation-induced silencing of tumor suppressors is common in cancer, reversal of promoter DNA hypermethylation by 5-aza-2'-deoxycytidine (decitabine), an FDA-approved DNA methyltransferase (DNMT) inhibitor, has proven effective in treating hematological neoplasms. However, its antitumor effect varies in solid tumors, stressing the importance of identifying biomarkers predictive of therapeutic response. Here, we focused on the identification of biomarkers to select decitabine-sensitive TNBC through increasing our understanding of the mechanism of decitabine action. We showed that protein levels of DNMTs correlated with response to decitabine in patient-derived xenograft (PDX) organoids originating from chemotherapy-sensitive and -resistant TNBCs, suggesting DNMT levels as potential biomarkers of response. Furthermore, all 3 methytransferases, DNMT1, DNMT3A, and DNMT3B, were degraded following low-concentration, long-term decitabine treatment both in vitro and in vivo. The DNMT proteins could be ubiquitinated by the E3 ligase, TNF receptor-associated factor 6 (TRAF6), leading to lysosome-dependent protein degradation. Depletion of TRAF6 blocked decitabine-induced DNMT degradation, conferring resistance to decitabine. Our study suggests a potential mechanism of regulating DNMT protein degradation and DNMT levels as response biomarkers for DNMT inhibitors in TNBCs.",
author = "Jia Yu and Bo Qin and Ann Moyer and Somaira Nowsheen and Tongzheng Liu and Sisi Qin and Yongxian Zhuang and Duan Liu and Lu, {Shijia W.} and Kalari, {Krishna R} and Visscher, {Daniel W} and Copland, {John A III} and McLaughlin, {Sarah A.} and {Moreno Aspitia}, Alvaro and Northfelt, {Donald W} and Gray, {Richard J.} and Zhenkun Lou and Suman, {Vera Jean} and Weinshilboum, {Richard M} and Boughey, {Judy C} and Goetz, {Matthew Philip} and Wang, {Liewei M}",
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T1 - DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine

AU - Yu, Jia

AU - Qin, Bo

AU - Moyer, Ann

AU - Nowsheen, Somaira

AU - Liu, Tongzheng

AU - Qin, Sisi

AU - Zhuang, Yongxian

AU - Liu, Duan

AU - Lu, Shijia W.

AU - Kalari, Krishna R

AU - Visscher, Daniel W

AU - Copland, John A III

AU - McLaughlin, Sarah A.

AU - Moreno Aspitia, Alvaro

AU - Northfelt, Donald W

AU - Gray, Richard J.

AU - Lou, Zhenkun

AU - Suman, Vera Jean

AU - Weinshilboum, Richard M

AU - Boughey, Judy C

AU - Goetz, Matthew Philip

AU - Wang, Liewei M

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis that lacks targeted therapies, especially in patients with chemotherapy-resistant disease. Since DNA methylation-induced silencing of tumor suppressors is common in cancer, reversal of promoter DNA hypermethylation by 5-aza-2'-deoxycytidine (decitabine), an FDA-approved DNA methyltransferase (DNMT) inhibitor, has proven effective in treating hematological neoplasms. However, its antitumor effect varies in solid tumors, stressing the importance of identifying biomarkers predictive of therapeutic response. Here, we focused on the identification of biomarkers to select decitabine-sensitive TNBC through increasing our understanding of the mechanism of decitabine action. We showed that protein levels of DNMTs correlated with response to decitabine in patient-derived xenograft (PDX) organoids originating from chemotherapy-sensitive and -resistant TNBCs, suggesting DNMT levels as potential biomarkers of response. Furthermore, all 3 methytransferases, DNMT1, DNMT3A, and DNMT3B, were degraded following low-concentration, long-term decitabine treatment both in vitro and in vivo. The DNMT proteins could be ubiquitinated by the E3 ligase, TNF receptor-associated factor 6 (TRAF6), leading to lysosome-dependent protein degradation. Depletion of TRAF6 blocked decitabine-induced DNMT degradation, conferring resistance to decitabine. Our study suggests a potential mechanism of regulating DNMT protein degradation and DNMT levels as response biomarkers for DNMT inhibitors in TNBCs.

AB - Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis that lacks targeted therapies, especially in patients with chemotherapy-resistant disease. Since DNA methylation-induced silencing of tumor suppressors is common in cancer, reversal of promoter DNA hypermethylation by 5-aza-2'-deoxycytidine (decitabine), an FDA-approved DNA methyltransferase (DNMT) inhibitor, has proven effective in treating hematological neoplasms. However, its antitumor effect varies in solid tumors, stressing the importance of identifying biomarkers predictive of therapeutic response. Here, we focused on the identification of biomarkers to select decitabine-sensitive TNBC through increasing our understanding of the mechanism of decitabine action. We showed that protein levels of DNMTs correlated with response to decitabine in patient-derived xenograft (PDX) organoids originating from chemotherapy-sensitive and -resistant TNBCs, suggesting DNMT levels as potential biomarkers of response. Furthermore, all 3 methytransferases, DNMT1, DNMT3A, and DNMT3B, were degraded following low-concentration, long-term decitabine treatment both in vitro and in vivo. The DNMT proteins could be ubiquitinated by the E3 ligase, TNF receptor-associated factor 6 (TRAF6), leading to lysosome-dependent protein degradation. Depletion of TRAF6 blocked decitabine-induced DNMT degradation, conferring resistance to decitabine. Our study suggests a potential mechanism of regulating DNMT protein degradation and DNMT levels as response biomarkers for DNMT inhibitors in TNBCs.

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