HDAC inhibitor suppresses proliferation and tumorigenicity of drug-resistant chronic myeloid leukemia stem cells through regulation of hsa-miR-196a targeting BCR/ABL1

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Failure to eradicate hematologic cancer stem cells (hCSCs) associated with resistance to tyrosine kinase inhibitors such as imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is a clinical challenge that highlights the need for discovering and developing therapeutic strategies that target and eliminate these hCSCs. Herein, we document the essential role of the interplay between histone deacetylases (HDACs), the polycomb group proteins, pluripotency transcription factors and the cell cycle machinery in the viability, oncogenicity and therapy evasion of IM-resistant CD34+/CD38- CML stem cells (CML-SCs). Using the proteotranscriptomic analyses of wild type (WT), CD34+/CD38+ and CD34+/CD38− K562 or KU812 cells, we showed that CD34+/CD38− SC-enriched cells expressed significantly higher levels of CD44, CD133, SOX2, Nanog, OCT4, and c-Myc mRNA and/or protein, compared to the WT or CD34+/CD38+ cells. This overexpression of stemness factors in the CD34+/CD38− cells positively correlates with enhanced expression of HDACs 1–6, cyclins D1/D3, CDK 2, 4 and 6, while inversely correlating with p18, p21 and p27. Enhanced co-expression of MDR1, survivin, and Bcl-2 proteins, supposedly involved in IM-resistance and CML-SC survival, was detected in both CD34+/CD38− and CD34+/CD38+ cells. Importantly, we demonstrate that in synergism with IM, SAHA reverses the tumor-promoting proteotranscriptomic profile noted above and elicits marked inhibition of the CML-SCs by up-regulating hsa-miR-196a expression. This hsa-miR-196a-mediated SC-limiting effect of SAHA is dose-dependent, low-dosed, cell cycle-modulating and accompanied by leukemic SC apoptosis. Interestingly, this anti-SC therapeutic activity of SAHA in vitro was reproduced in vivo using the NOD-SCID mice models.

Original languageEnglish
JournalExperimental Cell Research
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Myeloid Progenitor Cells
Histone Deacetylases
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Pharmaceutical Preparations
Neoplastic Stem Cells
Cell Cycle
Polycomb-Group Proteins
Cyclin D3
Inbred NOD Mouse
SCID Mice
Cyclin D1
Protein-Tyrosine Kinases
Proteins
Transcription Factors
Therapeutics
Apoptosis
Messenger RNA
Survival
Imatinib Mesylate
Neoplasms

Keywords

  • Chemoresistance
  • Chronic myeloid leukemia
  • HDAC inhibition
  • Hematopoietic stem cells
  • hsa-miR-196a
  • Imatinib
  • Myelogenous leukemia
  • SAHA

ASJC Scopus subject areas

  • Cell Biology

Cite this

@article{0b532039c45647e08042ae51f72248f4,
title = "HDAC inhibitor suppresses proliferation and tumorigenicity of drug-resistant chronic myeloid leukemia stem cells through regulation of hsa-miR-196a targeting BCR/ABL1",
abstract = "Failure to eradicate hematologic cancer stem cells (hCSCs) associated with resistance to tyrosine kinase inhibitors such as imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is a clinical challenge that highlights the need for discovering and developing therapeutic strategies that target and eliminate these hCSCs. Herein, we document the essential role of the interplay between histone deacetylases (HDACs), the polycomb group proteins, pluripotency transcription factors and the cell cycle machinery in the viability, oncogenicity and therapy evasion of IM-resistant CD34+/CD38- CML stem cells (CML-SCs). Using the proteotranscriptomic analyses of wild type (WT), CD34+/CD38+ and CD34+/CD38− K562 or KU812 cells, we showed that CD34+/CD38− SC-enriched cells expressed significantly higher levels of CD44, CD133, SOX2, Nanog, OCT4, and c-Myc mRNA and/or protein, compared to the WT or CD34+/CD38+ cells. This overexpression of stemness factors in the CD34+/CD38− cells positively correlates with enhanced expression of HDACs 1–6, cyclins D1/D3, CDK 2, 4 and 6, while inversely correlating with p18, p21 and p27. Enhanced co-expression of MDR1, survivin, and Bcl-2 proteins, supposedly involved in IM-resistance and CML-SC survival, was detected in both CD34+/CD38− and CD34+/CD38+ cells. Importantly, we demonstrate that in synergism with IM, SAHA reverses the tumor-promoting proteotranscriptomic profile noted above and elicits marked inhibition of the CML-SCs by up-regulating hsa-miR-196a expression. This hsa-miR-196a-mediated SC-limiting effect of SAHA is dose-dependent, low-dosed, cell cycle-modulating and accompanied by leukemic SC apoptosis. Interestingly, this anti-SC therapeutic activity of SAHA in vitro was reproduced in vivo using the NOD-SCID mice models.",
keywords = "Chemoresistance, Chronic myeloid leukemia, HDAC inhibition, Hematopoietic stem cells, hsa-miR-196a, Imatinib, Myelogenous leukemia, SAHA",
author = "Bamodu, {Oluwaseun Adebayo} and Kuo, {Kuang Tai} and Yuan, {Li Ping} and Cheng, {Wei Hong} and Lee, {Wei Hwa} and Ho, {Yuan Soon} and Chao, {Tsu Yi} and Yeh, {Chi Tai}",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.yexcr.2018.07.017",
language = "English",
journal = "Experimental Cell Research",
issn = "0014-4827",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - HDAC inhibitor suppresses proliferation and tumorigenicity of drug-resistant chronic myeloid leukemia stem cells through regulation of hsa-miR-196a targeting BCR/ABL1

AU - Bamodu, Oluwaseun Adebayo

AU - Kuo, Kuang Tai

AU - Yuan, Li Ping

AU - Cheng, Wei Hong

AU - Lee, Wei Hwa

AU - Ho, Yuan Soon

AU - Chao, Tsu Yi

AU - Yeh, Chi Tai

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Failure to eradicate hematologic cancer stem cells (hCSCs) associated with resistance to tyrosine kinase inhibitors such as imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is a clinical challenge that highlights the need for discovering and developing therapeutic strategies that target and eliminate these hCSCs. Herein, we document the essential role of the interplay between histone deacetylases (HDACs), the polycomb group proteins, pluripotency transcription factors and the cell cycle machinery in the viability, oncogenicity and therapy evasion of IM-resistant CD34+/CD38- CML stem cells (CML-SCs). Using the proteotranscriptomic analyses of wild type (WT), CD34+/CD38+ and CD34+/CD38− K562 or KU812 cells, we showed that CD34+/CD38− SC-enriched cells expressed significantly higher levels of CD44, CD133, SOX2, Nanog, OCT4, and c-Myc mRNA and/or protein, compared to the WT or CD34+/CD38+ cells. This overexpression of stemness factors in the CD34+/CD38− cells positively correlates with enhanced expression of HDACs 1–6, cyclins D1/D3, CDK 2, 4 and 6, while inversely correlating with p18, p21 and p27. Enhanced co-expression of MDR1, survivin, and Bcl-2 proteins, supposedly involved in IM-resistance and CML-SC survival, was detected in both CD34+/CD38− and CD34+/CD38+ cells. Importantly, we demonstrate that in synergism with IM, SAHA reverses the tumor-promoting proteotranscriptomic profile noted above and elicits marked inhibition of the CML-SCs by up-regulating hsa-miR-196a expression. This hsa-miR-196a-mediated SC-limiting effect of SAHA is dose-dependent, low-dosed, cell cycle-modulating and accompanied by leukemic SC apoptosis. Interestingly, this anti-SC therapeutic activity of SAHA in vitro was reproduced in vivo using the NOD-SCID mice models.

AB - Failure to eradicate hematologic cancer stem cells (hCSCs) associated with resistance to tyrosine kinase inhibitors such as imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients is a clinical challenge that highlights the need for discovering and developing therapeutic strategies that target and eliminate these hCSCs. Herein, we document the essential role of the interplay between histone deacetylases (HDACs), the polycomb group proteins, pluripotency transcription factors and the cell cycle machinery in the viability, oncogenicity and therapy evasion of IM-resistant CD34+/CD38- CML stem cells (CML-SCs). Using the proteotranscriptomic analyses of wild type (WT), CD34+/CD38+ and CD34+/CD38− K562 or KU812 cells, we showed that CD34+/CD38− SC-enriched cells expressed significantly higher levels of CD44, CD133, SOX2, Nanog, OCT4, and c-Myc mRNA and/or protein, compared to the WT or CD34+/CD38+ cells. This overexpression of stemness factors in the CD34+/CD38− cells positively correlates with enhanced expression of HDACs 1–6, cyclins D1/D3, CDK 2, 4 and 6, while inversely correlating with p18, p21 and p27. Enhanced co-expression of MDR1, survivin, and Bcl-2 proteins, supposedly involved in IM-resistance and CML-SC survival, was detected in both CD34+/CD38− and CD34+/CD38+ cells. Importantly, we demonstrate that in synergism with IM, SAHA reverses the tumor-promoting proteotranscriptomic profile noted above and elicits marked inhibition of the CML-SCs by up-regulating hsa-miR-196a expression. This hsa-miR-196a-mediated SC-limiting effect of SAHA is dose-dependent, low-dosed, cell cycle-modulating and accompanied by leukemic SC apoptosis. Interestingly, this anti-SC therapeutic activity of SAHA in vitro was reproduced in vivo using the NOD-SCID mice models.

KW - Chemoresistance

KW - Chronic myeloid leukemia

KW - HDAC inhibition

KW - Hematopoietic stem cells

KW - hsa-miR-196a

KW - Imatinib

KW - Myelogenous leukemia

KW - SAHA

UR - http://www.scopus.com/inward/record.url?scp=85049897287&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049897287&partnerID=8YFLogxK

U2 - 10.1016/j.yexcr.2018.07.017

DO - 10.1016/j.yexcr.2018.07.017

M3 - Article

JO - Experimental Cell Research

JF - Experimental Cell Research

SN - 0014-4827

ER -