Histone deacetylase inhibitors stimulate dedifferentiation of human breast cancer cells through WNT/β-catenin signaling.
Histone deacetylase inhibitors stimulate dedifferentiation of human breast cancer cells through WNT/β-catenin signaling.
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DOI：
10.1002/stem.1219
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Woodward WA
中科院分区：
文献类型：
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作者：
Debeb BG;Lacerda L;Xu W;Larson R;Solley T;Atkinson R;Sulman EP;Ueno NT;Krishnamurthy S;Reuben JM;Buchholz TA;Woodward WA
最近的研究表明，分化的癌细胞可以去分化为癌症干细胞(CSCs)，尽管到目前为止还没有研究报告这种转变是否受到全身抗癌药物的影响。丙戊酸(VA)是一种组蛋白脱乙酰酶(HDAC)抑制剂，可促进造血干细胞的自我更新和扩增，并促进体细胞生成诱导的多能干细胞，目前正在进行乳腺癌临床试验。我们假设，HDAC抑制剂将分化的癌细胞重新编程为更耐药的干细胞样状态。根据ALDH活性对两个高侵袭性的乳腺癌细胞株SUM159和MDA-231进行FACS分选，然后用两种已知的HDAC抑制剂之一VA或SAHA(Suberoylanilide异羟肟酸)处理ALDH阴性和ALDH阳性的细胞。此外，转移性乳腺癌患者的原代肿瘤细胞在用HDAC抑制剂治疗后进行了ALDH活性评估。我们证明了单个细胞分选的ALDH阴性细胞在体外自发产生ALDH阳性细胞。用HDAC抑制剂处理ALDH阴性细胞，可促进ALDH阳性细胞的扩增，提高乳房形成效率。最重要的是，在有限稀释生长试验中，它显著增加了ALDH阴性细胞的肿瘤启动能力。此外，当HDAC抑制剂上调β-连环蛋白的表达并显著增加WNT报告基因活性时，TCF4显性负性结构可抑制HDAC抑制剂诱导的CSCs的扩张。这些结果表明，HDAC抑制剂通过去分化促进乳腺CSCs的扩张，对HDAC抑制剂在癌症治疗中的应用具有重要的临床意义。
Recent studies have shown that differentiated cancer cells can de-differentiate into cancer stem cells (CSCs) although to date no studies have reported whether this transition is influenced by systemic anti-cancer agents. Valproic acid (VA) is a histone deacetylase (HDAC) inhibitor that promotes self renewal and expansion of hematopietic stem cells and facilitates the generation of induced pluripotent stem cells from somatic cells and is currently being investigated in breast cancer clinical trials. We hypothesized that HDAC inhibitors reprogram differentiated cancer cells towards the more resistant stem cell-like state. Two highly aggressive breast cancer cell lines, SUM159 and MDA-231, were FACS-sorted based on ALDH activity and subsequently ALDH-negative and ALDH-positive cells were treated with one of two known HDAC inhibitors, VA or SAHA (suberoylanilide hydroxamic acid). In addition, primary tumor cells from patients with metastatic breast cancer were evaluated for ALDH activity following treatment with HDAC inhibitors. We demonstrate that single cell sorted ALDH- negative cells spontaneously generated ALDH-positive cells in vitro. Treatment of ALDH-negative cells with HDAC inhibitors promoted the expansion of ALDH-positive cells and increased mammosphere forming efficiency. Most importantly, it significantly increased the tumor-initiating capacity of ALDH- negative cells in limiting dilution outgrowth assays. Moreover, while HDAC inhibitors upregulated β-catenin expression and significantly increased WNT reporter activity, a TCF4 dominant negative construct abolished HDAC-inhibitor induced expansion of CSCs. These results demonstrate that HDAC inhibitors promote the expansion of breast CSCs through dedifferentiation and have important clinical implications for the use of HDAC inhibitors in the treatment of cancer.