Homeobox gene <it>Rhox5 </it>is regulated by epigenetic mechanisms in cancer and stem cells and promotes cancer growth

• Main Authors: O'Malley Mark E, Li Qiang, Bartlett David L, Guo Z Sheng
• Format: Article
• Language: English
• Published: BMC 2011-05-01
• Series: Molecular Cancer
• Online Access: http://www.molecular-cancer.com/content/10/1/63

<p>Abstract</p> <p>Background</p> <p>Homeobox genes murine <it>Rhox5 </it>and human <it>RHOXF1 </it>are expressed in early embryonic stages and then mostly restricted to germline tissues in normal adult, yet they are aberrantly expressed in cancer cells <it>in vitro </it>and <it>in vivo </it>. Here we study the epigenetic regulation and potential functions of <it>Rhox5 </it>gene.</p> <p>Findings</p> <p>In <it>Rhox5 </it>-silenced or extremely low expresser cells, we observed low levels of active histone epigenetic marks (H3ac, H4ac and H3K4me2) and high levels of repressive mark H3K9me2 along with DNA hypermethylation in the promoter. In <it>Rhox5 </it>low expresser cells, we typically observed modest levels of both active and repressive histone marks along with moderate DNA methylation. In <it>Rhox5 </it>highly expressed CT26 cancer cells, we observed DNA hypomethylation along with high levels of both active and repressive histone marks. Epigenetic drugs (retinoic acid and MS-275) induced F9 cell differentiation with enhanced <it>Rhox5 </it>expression and dynamic changes of epigenetic marks. Finally, <it>Rhox5 </it>knockdown by small hairpin RNA (shRNA) in CT26 colon cancer decreased cell proliferation and migration <it>in vitro </it>and tumor growth <it>in vivo </it>.</p> <p>Conclusions</p> <p>Both DNA methylation and histone methylation/acetylation play key roles in modulating <it>Rhox5 </it>expression in various cell types. The stem cell-like "bivalent domain", an epigenetic feature originally identified in key differentiation genes within stem cells, exists in the <it>Rhox5 </it>gene promoter in not only embryonic stem cells but also cancer cells, cancer stem cells, and differentiated Sertoli cells. As <it>Ras </it>signaling-dependent <it>Rhox5 </it>expression promotes tumor growth, <it>Rhox5 </it>may be an ideal target for therapeutic intervention in cancer.</p>