Identification of a Small-Molecule Inhibitor That Disrupts the SIX1/EYA2 Complex, EMT, and Metastasis.
Animals
Antineoplastic Agents
/ pharmacology
BRCA1 Protein
/ metabolism
Breast Neoplasms
/ drug therapy
Epithelial-Mesenchymal Transition
/ drug effects
Female
Gene Expression Regulation, Neoplastic
/ drug effects
Homeodomain Proteins
/ antagonists & inhibitors
Humans
Intracellular Signaling Peptides and Proteins
/ antagonists & inhibitors
Kaplan-Meier Estimate
MCF-7 Cells
Mice
Neoplasm Metastasis
/ prevention & control
Nuclear Proteins
/ antagonists & inhibitors
Protein Binding
/ drug effects
Protein Tyrosine Phosphatases
/ antagonists & inhibitors
RNA-Seq
Signal Transduction
/ drug effects
Xenograft Model Antitumor Assays
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 06 2020
15 06 2020
Historique:
received:
07
02
2020
revised:
19
03
2020
accepted:
22
04
2020
pubmed:
29
4
2020
medline:
11
11
2020
entrez:
29
4
2020
Statut:
ppublish
Résumé
Metastasis is the major cause of mortality for patients with cancer, and dysregulation of developmental signaling pathways can significantly contribute to the metastatic process. The Sine oculis homeobox homolog 1 (SIX1)/eyes absent (EYA) transcriptional complex plays a critical role in the development of multiple organs and is typically downregulated after development is complete. In breast cancer, aberrant expression of SIX1 has been demonstrated to stimulate metastasis through activation of TGFβ signaling and subsequent induction of epithelial-mesenchymal transition (EMT). In addition, SIX1 can induce metastasis via non-cell autonomous means, including activation of GLI-signaling in neighboring tumor cells and activation of VEGFC-induced lymphangiogenesis. Thus, targeting SIX1 would be expected to inhibit metastasis while conferring limited side effects. However, transcription factors are notoriously difficult to target, and thus novel approaches to inhibit their action must be taken. Here we identified a novel small molecule compound, NCGC00378430 (abbreviated as 8430), that reduces the SIX1/EYA2 interaction. 8430 partially reversed transcriptional and metabolic profiles mediated by SIX1 overexpression and reversed SIX1-induced TGFβ signaling and EMT. 8430 was well tolerated when delivered to mice and significantly suppressed breast cancer-associated metastasis
Identifiants
pubmed: 32341035
pii: 0008-5472.CAN-20-0435
doi: 10.1158/0008-5472.CAN-20-0435
pmc: PMC7510951
mid: NIHMS1589489
doi:
Substances chimiques
Antineoplastic Agents
0
BRCA1 Protein
0
BRCA1 protein, human
0
Homeodomain Proteins
0
Intracellular Signaling Peptides and Proteins
0
Nuclear Proteins
0
SIX1 protein, human
0
EYA2 protein, human
EC 3.1.3.48
Protein Tyrosine Phosphatases
EC 3.1.3.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2689-2702Subventions
Organisme : NINDS NIH HHS
ID : R01 NS108396
Pays : United States
Organisme : NIH HHS
ID : K01 OD022982
Pays : United States
Organisme : NIDA NIH HHS
ID : R03 DA033174
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA224867
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046934
Pays : United States
Organisme : NCI NIH HHS
ID : F99 CA234940
Pays : United States
Organisme : NCI NIH HHS
ID : K00 CA234940
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007635
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA185752
Pays : United States
Organisme : NIH HHS
ID : S10 OD027023
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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