TY - JOUR
T1 - Anti-metastatic activity of MPT0G211, a novel HDAC6 inhibitor, in human breast cancer cells in vitro and in vivo
AU - Hsieh, Yi Ling
AU - Tu, Huang Ju
AU - Pan, Shiow Lin
AU - Liou, Jing Ping
AU - Yang, Chia Ron
N1 - Copyright © 2019 Elsevier B.V. All rights reserved.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Triple-negative breast cancer (TNBC) is associated with an increased risk of metastasis and a poor prognosis. The invasive ability of TNBC relies on actin reorganization and is regulated by histone deacetylase 6 (HDAC6). The present study aimed to examine the effect of MPT0G211, a novel HDAC6 inhibitor, on cell migration and microtubule association in both in vitro and in vivo models of TNBC. Here MPT0G211 more selectively and potently targeted and inhibited HDAC6, compared with tubastatin A, another selective HDAC6 inhibitor. In vitro, MPT0G211 decreased the migration of the TNBC cell line MDA-MB-231, particularly when administered together with paclitaxel, and increased heat shock protein 90 (Hsp90) acetylation, leading to the dissociation of Hsp90 from aurora-A and proteasomal degradation. Furthermore, MPT0G211 significantly disrupted F-actin polymerization by increasing cortactin acetylation and downregulating slingshot protein phosphatase 1 (SSH1) and active cofilin expression. In vivo, MPT0G211 treatment significantly ameliorated TNBC metastasis. In conclusion, our results demonstrate that MPT0G211 reduces TNBC cell motility by promoting cortactin acetylation and aurora-A degradation, and inhibiting the cofilin–F-actin pathway via HDAC6 activity attenuation. MPT0G211 therefore demonstrates therapeutic potential for invasive TNBC.
AB - Triple-negative breast cancer (TNBC) is associated with an increased risk of metastasis and a poor prognosis. The invasive ability of TNBC relies on actin reorganization and is regulated by histone deacetylase 6 (HDAC6). The present study aimed to examine the effect of MPT0G211, a novel HDAC6 inhibitor, on cell migration and microtubule association in both in vitro and in vivo models of TNBC. Here MPT0G211 more selectively and potently targeted and inhibited HDAC6, compared with tubastatin A, another selective HDAC6 inhibitor. In vitro, MPT0G211 decreased the migration of the TNBC cell line MDA-MB-231, particularly when administered together with paclitaxel, and increased heat shock protein 90 (Hsp90) acetylation, leading to the dissociation of Hsp90 from aurora-A and proteasomal degradation. Furthermore, MPT0G211 significantly disrupted F-actin polymerization by increasing cortactin acetylation and downregulating slingshot protein phosphatase 1 (SSH1) and active cofilin expression. In vivo, MPT0G211 treatment significantly ameliorated TNBC metastasis. In conclusion, our results demonstrate that MPT0G211 reduces TNBC cell motility by promoting cortactin acetylation and aurora-A degradation, and inhibiting the cofilin–F-actin pathway via HDAC6 activity attenuation. MPT0G211 therefore demonstrates therapeutic potential for invasive TNBC.
KW - Aurora-A
KW - Cell migration
KW - F-actin
KW - Histone deacetylase 6
KW - Paclitaxel
KW - Triple-negative breast cancer
KW - Aurora Kinase A/metabolism
KW - Cell Movement/drug effects
KW - Humans
KW - HSP90 Heat-Shock Proteins/metabolism
KW - Cell Survival/drug effects
KW - MCF-7 Cells
KW - Triple Negative Breast Neoplasms/drug therapy
KW - Female
KW - Histone Deacetylase Inhibitors/administration & dosage
KW - Antineoplastic Combined Chemotherapy Protocols/administration & dosage
KW - Acetylation/drug effects
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Neoplasm Metastasis/drug therapy
KW - Drug Synergism
KW - Xenograft Model Antitumor Assays
KW - Animals
KW - Paclitaxel/administration & dosage
KW - Cell Line, Tumor
KW - Mice
UR - http://www.scopus.com/inward/record.url?scp=85063034700&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063034700&partnerID=8YFLogxK
U2 - 10.1016/j.bbamcr.2019.03.003
DO - 10.1016/j.bbamcr.2019.03.003
M3 - Article
C2 - 30867138
AN - SCOPUS:85063034700
SN - 0167-4889
VL - 1866
SP - 992
EP - 1003
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 6
ER -