TWIST1-WDR5-hottip regulates Hoxa9 chromatin to facilitate prostate cancer metastasis

Reem Malek, Rajendra P. Gajula, Russell D. Williams, Belinda Nghiem, Brian W. Simons, Katriana Nugent, Hailun Wang, Kekoa Taparra, Ghali Lemtiri-Chlieh, Arum R. Yoon, Lawrence True, Steven S. An, Theodore L. DeWeese, Ashley E. Ross, Edward M. Schaeffer, Kenneth J. Pienta, Paula J. Hurley, Colm Morrissey, Phuoc T. Tran*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

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 onWDR5. Expression ofWDR5 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 in vitro and metastasis in vivo. 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.

Original languageEnglish (US)
Pages (from-to)3181-3193
Number of pages13
JournalCancer Research
Volume77
Issue number12
DOIs
StatePublished - Jun 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'TWIST1-WDR5-hottip regulates Hoxa9 chromatin to facilitate prostate cancer metastasis'. Together they form a unique fingerprint.

Cite this