Anti-cancer STEM cells – from China with love

Dr. Weeks’ Comment: Now that everyone but your oncologist is paying attention to attacking cancer STEM cells rather than the easier and less dangerous cancer TUMOR cells,  exciting and promising agents like lysine-specific demethylase-1 (LSD1) are being developed. (See below).  I have lectured at professional conferences over the past 6 years on the topic of how to target cancer STEM cell and more doctors (especially in Japan)  are adopting my “centisble” (safe, effective and cost effective) protocols of Corrective Cancer Care. We have already posted articles about agents which target cancer STEM cells and we hope you will encourage your oncologist to focus here, on the real danger, the cancer STEM cell and stop wasting your life forces and money targeting cancer TUMOR cells.



Novel Histone Demethylase LSD1 Inhibitors Selectively Target Cancer Cells with Pluripotent Stem Cell Properties

.    Jing Wang1,4, Fei Lu1,4, Qi Ren1, Hong Sun4, Zhengshuang Xu1, Rongfeng Lan1, Yuqing Liu2, David Ward3, Junmin Quan1, Tao Ye1,2, and Hui Zhang1,4



Histone modification determines epigenetic patterns of gene expression with methylation of histone H3 at lysine 4 (H3K4) often associated with active promoters. LSD1/KDM1 is a histone demethylase that suppresses gene expression by converting dimethylated H3K4 to mono- and unmethylated H3K4. LSD1 is essential for metazoan development, but its pathophysiologic functions in cancer remain mainly uncharacterized. In this study, we developed specific bioactive small inhibitors of LSD1 that enhance H3K4 methylation and derepress epigenetically suppressed genes in vivo. Strikingly, these compounds inhibited the proliferation of pluripotent cancer cells including teratocarcinoma, embryonic carcinoma, and seminoma or embryonic stem cells that express the stem cell markers Oct4 and Sox2 while displaying minimum growth-inhibitory effects on non-pluripotent cancer or normal somatic cells. RNA interference-mediated knockdown of LSD1 expression phenocopied these effects, confirming the specificity of small molecules and further establishing the high degree of sensitivity and selectivity of pluripotent cancer cells to LSD1 ablation. In support of these results, we found that LSD1 protein level is highly elevated in pluripotent cancer cells and in human testicular seminoma tissues that express Oct4. Using these novel chemical inhibitors as probes, our findings establish LSD1 and histone H3K4 methylation as essential cancer-selective epigenetic targets in cancer cells that have pluripotent stem cell properties. Cancer Res; 71(23); 7238-49. ©2011 AACR.

Footnotes Note: Supplementary data for this article are available at Cancer Research Online (




LSD1 Regulates Pluripotency of Embryonic Stem/Carcinoma Cells through Histone Deacetylase 1-Mediated Deacetylation of Histone H4 at Lysine 16


.    Feng Yina, Rongfeng Lana, Xiaoming Zhanga, Linyu Zhua, Fangfang Chena, Zhengshuang Xua, Yuqing Liub, Tao Yeb, Hong Sunc, Fei Lua and Hui Zhanga,c



LSD1 is essential for the maintenance of pluripotency of embryonic stem (ES) or embryonic carcinoma/teratocarcinoma (EC) cells. We have previously developed novel LSD1 inhibitors that selectively inhibit ES/EC cells. However, the critical targets of LSD1 remain unclear. Here, we found that LSD1 interacts with histone deacetylase 1 (HDAC1) to regulate the proliferation of ES/EC cells through acetylation of histone H4 at lysine 16 (H4K16), which we show is a critical substrate of HDAC1. The LSD1 demethylase and HDAC1 deacetylase activities were both inactivated if one of them in the complex was chemically inhibited in ES/EC cells or in reconstituted protein complexes. Loss of HDAC1 phenocopied the selective growth-inhibitory effects and increased the levels of H3K4 methylation and H4K16 acetylation of LSD1 inactivation on ES/EC cells. Reduction of acetylated H4K16 by ablation of the acetyltransferase males absent on the first (MOF) is sufficient to rescue the growth inhibition induced by LSD1 inactivation. While LSD1 or HDAC1 inactivation caused the downregulation of Sox2 and Oct4 and induction of differentiation genes, such as FOXA2 or BMP2, depletion of MOF restored the levels of Sox2, Oct4, and FoxA2 in LSD1-deficient cells. Our studies reveal a novel mechanism by which LSD1 acts through the HDAC1- and MOF-mediated regulation of H4K16 acetylation to maintain the pluripotency of ES/EC cells.



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