TWIST1-WDR5-Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis

Abstract

TWIST1 is a transcription factor critical for development which can promote prostate cancer metastasis. During embryonic development, TWIST1 and HOXA9 are co-expressed in mouse prostate and then silenced post-natally. Here we report that TWIST1 and HOXA9 co-expression are re-activated 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 co-enrichment of TWIST1 and WDR5 as well 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. Pharmacological 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.

Targeting HOX/PBX dimer formation as a potential therapeutic option in esophageal squamous cell carcinoma

“…To elucidate their significance in ESCC, it is necessary to clarify the association between their expression patterns and patient prognosis. It was shown that the survival time of patients with high HOXB7 or HOXC6 or HOXC8 expression was significantly shorter than that of patients with low expression, which is similar to the results of other groups . As reported, the consequences of dysregulated HOX genes in carcinogenesis can be interpreted as an extension of their normal function .…”

“…It was shown that the survival time of patients with high HOXB7 or HOXC6 or HOXC8 expression was significantly shorter than that of patients with low expression, which is similar to the results of other groups. [27][28][29] As reported, the consequences of dysregulated HOX genes in carcinogenesis can be interpreted as an extension of their normal function. [30][31][32] Given that HOX genes can be viewed as global regulators of growth and differentiation, we investigated whether they could modulate the malignant phenotype in es- Consequently, it becomes difficult to interpret these data and determine the exact contribution of any of these individual genes to a malignant phenotype.…”

Long noncoding RNA HOTTIP mediates SRF expression through sponging miR‐150 in hepatic stellate cells

“…Increasing evidence indicates that HOTTIP is overexpressed in prostate cancer, lung cancer, and pancreatic cancer . HOTTIP knockdown impedes cell viability, proliferation, invasion, and angiogenesis in human cancer cells, therefore it is been identified as an oncogenic long noncoding RNA (lncRNA).…”

Molecular functions and biological roles of long non‐coding RNAs in human physiology and disease

“…Chromosomal looping of this locus brings the HOXA genes into close proximity to HOTTIP , which activates the expression of the predominantly 5′ located HOXA genes. Interestingly, the deregulation of HOXA genes by HOTTIP has been implicated in the development and progression of prostate cancer, as well as in the clinical disease progression of hepatocellular carcinoma patients . Mechanistically, HOTTIP has been suggested to specifically interact with the lysine methyltransferase complex WDR5‐MLL to facilitate histone 3 lysine 4 trimethylation (H3K4me3) and hence transcriptional activation of this locus .…”

“…Interestingly, the deregulation of HOXA genes by HOTTIP has been implicated in the development and progression of prostate cancer, as well as in the clinical disease progression of hepatocellular carcinoma patients. 25,26 Mechanistically, HOTTIP has been suggested to specifically interact with the lysine methyltransferase complex WDR5-MLL to facilitate histone 3 lysine 4 trimethylation (H3K4me3) and hence transcriptional activation of this locus. 24,27 However, the specificity and in vivo relevance of this RNA-protein interaction is still unclear because all of the studies conducted so far comprise either in vitro RNA pulldown or native RNA immunoprecipitation experiments, which are both known to be prone to return falsepositive RNA-protein interactions.…”