Targeting HOX transcription factors in prostate cancer.
BACKGROUND
The HOX genes are a family of transcription factors that help to determine cell and tissue identity during early development, and which are also over-expressed in a number of malignancies where they have been shown to promote cell proliferation and survival. The purpose of this study was to evaluate the expression of HOX genes in prostate cancer and to establish whether prostate cancer cells are sensitive to killing by HXR9, an inhibitor of HOX function.


METHODS
HOX function was inhibited using the HXR9 peptide. HOX gene expression was assessed by RNA extraction from cells or tissues followed by quantitative PCR, and siRNA was used to block the expression of the HOX target gene, cFos. In vivo modelling involved a mouse flank tumour induced by inoculation with LNCaP cells.


RESULTS
In this study we show that the expression of HOX genes in prostate tumours is greatly increased with respect to normal prostate tissue. Targeting the interaction between HOX proteins and their PBX cofactor induces apoptosis in the prostate cancer derived cell lines PC3, DU145 and LNCaP, through a mechanism that involves a rapid increase in the expression of cFos, an oncogenic transcription factor. Furthermore, disrupting HOX/PBX binding using the HXR9 antagonist blocks the growth of LNCaP tumours in a xenograft model over an extended period.


CONCLUSIONS
Many HOX genes are highly over-expressed in prostate cancer, and prostate cancer cells are sensitive to killing by HXR9 both in vitro and in vivo. The HOX genes are therefore a potential therapeutic target in prostate cancer.
Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK. r.morgan@surrey.ac.uk.
Richard
R
Morgan
Angie
A
Boxall
Kevin J
KJ
Harrington
Guy R
GR
Simpson
Agnieszka
A
Michael
Hardev S
HS
Pandha
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods; D010455:Peptides / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C522972:HXR9 peptide; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D014157:Transcription Factors