Transcription factor Oct1 is a somatic and cancer stem cell determinant.
Transcription factor Oct1 is a somatic and cancer stem cell determinant.
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DOI：
10.1371/journal.pgen.1003048
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Tantin D
中科院分区：
文献类型：
--
作者：
Maddox J;Shakya A;South S;Shelton D;Andersen JN;Chidester S;Kang J;Gligorich KM;Jones DA;Spangrude GJ;Welm BE;Tantin D
确定控制体细胞和癌症干细胞身份的主转录因子是一个重要的目标。在这里，我们展示了Oct4平行Oct1，一个涉及应激反应，代谢控制和平衡转录状态的转录因子，调节正常和病理干细胞功能。结肠和小肠中的Oct1HI细胞共同表达已知的干细胞标记物。在原发性恶性组织中，高Oct1蛋白而非mRNA水平与CD24LOCD44HI癌起始细胞的频率密切相关。通过RNAi降低Oct1的表达降低了ALDHHI和染料外排hi细胞的比例，增加Oct1增加了ALDHHI细胞的比例。正常ALDHHI细胞含有升高的Oct1蛋白，但没有mRNA水平。在功能上，我们发现Oct1在竞争性和连续移植中促进肿瘤植入频率和促进造血干细胞植入潜力。除了先前描述的Oct1转录靶点外，我们还确定了四个与干细胞表型相关的Oct1靶点。总的来说，这些数据表明Oct1调节正常和癌症干细胞的功能。了解控制干细胞功能的机制是将干细胞充分应用于再生医学以及充分理解干细胞与癌症之间关系的基本前提。在这项研究中，我们发现一种被称为Oct1的转录因子是正常和癌症干细胞功能的中枢调节因子。我们发现高Oct1水平与多种正常和恶性情况下的干细胞相关。上调或下调Oct1表达，相应地改变了多种干细胞参数以及干细胞功能。我们强调并确定了Oct1结合的新靶基因，这些基因与干细胞功能中的作用一致。
Defining master transcription factors governing somatic and cancer stem cell identity is an important goal. Here we show that the Oct4 paralog Oct1, a transcription factor implicated in stress responses, metabolic control, and poised transcription states, regulates normal and pathologic stem cell function. Oct1HI cells in the colon and small intestine co-express known stem cell markers. In primary malignant tissue, high Oct1 protein but not mRNA levels strongly correlate with the frequency of CD24LOCD44HI cancer-initiating cells. Reducing Oct1 expression via RNAi reduces the proportion of ALDHHI and dye effluxHI cells, and increasing Oct1 increases the proportion of ALDHHI cells. Normal ALDHHI cells harbor elevated Oct1 protein but not mRNA levels. Functionally, we show that Oct1 promotes tumor engraftment frequency and promotes hematopoietic stem cell engraftment potential in competitive and serial transplants. In addition to previously described Oct1 transcriptional targets, we identify four Oct1 targets associated with the stem cell phenotype. Cumulatively, the data indicate that Oct1 regulates normal and cancer stem cell function. Understanding the mechanisms that control stem cell function is a fundamental prerequisite both for the full application of stem cells to regenerative medicine and for a full understanding of the relationship between stem cells and cancer. In this study we show that a transcription factor known as Oct1 is a central regulator of normal and cancer stem cell function. We show that high Oct1 levels are associated with stem cells in multiple normal and malignant settings. Altering Oct1 expression, up or down, correspondingly alters multiple stem cell parameters, as well as stem cell function. We highlight known and identify new target genes Oct1 binds to that are consistent with a role in stem cell function.
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影响因子：
11.2
作者：
Huang EH;Hynes MJ;Zhang T;Ginestier C;Dontu G;Appelman H;Fields JZ;Wicha MS;Boman BM
通讯作者：
Boman BM
影响因子：
11.2
作者：
Charafe-Jauffret E;Ginestier C;Iovino F;Wicinski J;Cervera N;Finetti P;Hur MH;Diebel ME;Monville F;Dutcher J;Brown M;Viens P;Xerri L;Bertucci F;Stassi G;Dontu G;Birnbaum D;Wicha MS
通讯作者：
Wicha MS
影响因子：
3.7
作者：
Kang J;Goodman B;Zheng Y;Tantin D
通讯作者：
Tantin D
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.2
作者：
Broadley, Kate W. R.;Hunn, Martin K.;McConnell, Melanie J.
通讯作者：
McConnell, Melanie J.