Combined Inhibition of DNMT and HDAC Blocks the Tumorigenicity of Cancer Stem-like Cells and Attenuates Mammary Tumor Growth.
Combined Inhibition of DNMT and HDAC Blocks the Tumorigenicity of Cancer Stem-like Cells and Attenuates Mammary Tumor Growth.
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DOI：
10.1158/0008-5472.can-15-2249
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发表时间：
2016-06-01
期刊：
影响因子：
11.2
通讯作者：
Thangaraju M
中科院分区：
文献类型：
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作者：
Pathania R;Ramachandran S;Mariappan G;Thakur P;Shi H;Choi JH;Manicassamy S;Kolhe R;Prasad PD;Sharma S;Lokeshwar BL;Ganapathy V;Thangaraju M
近年来，在乳腺干细胞和肿瘤干细胞(CSCs)的分离和验证方面取得了令人印象深刻的技术进步，但调控干细胞自我更新的信号通路在很大程度上尚不清楚。此外，CSCs被认为对化疗和放射耐药有贡献。在这项研究中，我们使用MMTV-Neu-TG小鼠乳腺肿瘤模型来确定潜在的消除CSCs的新策略。我们发现腔前体细胞和基础干细胞都容易受到遗传和表观遗传修饰的影响，这促进了致癌转化和致瘤潜力。DNMT抑制剂5-氮胞苷和HDAC抑制剂丁酸盐的联合使用显着降低了CSC的丰度，并提高了小鼠的总体存活率。5-氮杂胞苷+丁酸盐处理的CSCs的RNA-SEQ分析表明，染色质修饰物的抑制阻断了促进生长的信号分子如RAD51AP1和SPC25，这两个分子在DNA损伤修复和动粒组装中发挥关键作用。此外，RAD51AP1和SPC25在人类乳腺肿瘤组织中显著过度表达，并与患者总体生存率下降有关。总之，我们的研究表明，乳腺CSCs对遗传和表观遗传修饰具有内在的敏感性，因此可能会受到基于表观遗传的治疗方法的显著影响，因此有必要进一步研究DNMT和HDAC联合抑制难治性或耐药乳腺癌的作用。
Recently, impressive technical advancements have been made in the isolation and validation of mammary stem cells and cancer stem cells (CSCs), but the signaling pathways that regulate stem cell self-renewal are largely unknown. Further, CSCs are believed to contribute to chemo- and radioresistance. In this study, we used the MMTV-Neu-Tg mouse mammary tumor model to identify potential new strategies for eliminating CSCs. We found that both luminal progenitor and basal stem cells are susceptible to genetic and epigenetic modifications, which facilitate oncogenic transformation and tumorigenic potential. A combination of the DNMT inhibitor 5-azacytidine and the HDAC inhibitor butyrate markedly reduced CSC abundance and increased the overall survival in this mouse model. RNA-seq analysis of CSCs treated with 5-azacytidine plus butyrate provided evidence that inhibition of chromatin modifiers blocks growth-promoting signaling molecules such as RAD51AP1 and SPC25, which play key roles in DNA damage repair and kinetochore assembly. Moreover, RAD51AP1 and SPC25 were significantly overexpressed in human breast tumor tissues and were associated with reduced overall patient survival. In conclusion, our studies suggest that breast CSCs are intrinsically sensitive to genetic and epigenetic modifications and can therefore be significantly affected by epigenetic-based therapies, warranting further investigation of combined DNMT and HDAC inhibition in refractory or drug-resistant breast cancer.