Cancer research (Chicago, Ill.), 2017-06, Vol.77 (12), p.3181-3193
2017
Details
- Autor(en) / Beteiligte
- Titel
- TWIST1-WDR5- Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis
- Ist Teil von
- Cancer research (Chicago, Ill.), 2017-06, Vol.77 (12), p.3181-3193
- Ort / Verlag
- United States: American Association for Cancer Research, Inc
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- TWIST1 is a transcription factor critical for development that can promote prostate cancer metastasis. During embryonic development, TWIST1 and HOXA9 are coexpressed in mouse prostate and then silenced postnatally. Here we report that TWIST1 and HOXA9 coexpression are reactivated in mouse and human primary prostate tumors and are further enriched in human metastases, correlating with survival. TWIST1 formed a complex with WDR5 and the lncRNA Hottip/HOTTIP, members of the MLL/COMPASS-like H3K4 methylases, which regulate chromatin in the Hox/HOX cluster during development. TWIST1 overexpression led to coenrichment of TWIST1 and WDR5 as well as increased H3K4me3 chromatin at the Hoxa9/HOXA9 promoter, which was dependent on WDR5. Expression of WDR5 and Hottip/HOTTIP was also required for TWIST1-induced upregulation of HOXA9 and aggressive cellular phenotypes such as invasion and migration. Pharmacologic inhibition of HOXA9 prevented TWIST1-induced aggressive prostate cancer cellular phenotypes and metastasis This study demonstrates a novel mechanism by which TWIST1 regulates chromatin and gene expression by cooperating with the COMPASS-like complex to increase H3K4 trimethylation at target gene promoters. Our findings highlight a TWIST1-HOXA9 embryonic prostate developmental program that is reactivated during prostate cancer metastasis and is therapeutically targetable. .
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0008-5472eISSN: 1538-7445DOI: 10.1158/0008-5472.can-16-2797Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5489316
- Format
- –
- Schlagworte
- Animals, Blotting, Western, Cancer, Cell Line, Tumor, Cell migration, Chromatin, DNA methylation, Embryogenesis, Embryonic growth stage, Fluorescent Antibody Technique, Gene expression, Gene Expression Regulation, Neoplastic - genetics, Gene Knockout Techniques, Heterografts, Histone-Lysine N-Methyltransferase - genetics, Histone-Lysine N-Methyltransferase - metabolism, Homeodomain Proteins - genetics, Homeodomain Proteins - metabolism, Humans, Immunohistochemistry, Immunoprecipitation, Leukocyte migration, Male, Metastases, Metastasis, Methylation, Mice, Migration, Neoplasm Invasiveness - genetics, Neoplasm Invasiveness - pathology, Nuclear Proteins - genetics, Nuclear Proteins - metabolism, Polymerase Chain Reaction, Prostate, Prostate cancer, Prostatic Neoplasms - genetics, Prostatic Neoplasms - pathology, RNA, Long Noncoding - genetics, RNA, Long Noncoding - metabolism, Tumors, Twist-Related Protein 1 - genetics, Twist-Related Protein 1 - metabolism