Runx1 Role in Epithelial and Cancer Cell Proliferation Implicates Lipid Metabolism and Scd1 and Soat1 Activity.
Runx1 Role in Epithelial and Cancer Cell Proliferation Implicates Lipid Metabolism and Scd1 and Soat1 Activity.
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DOI：
10.1002/stem.2868
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Tumbar T
中科院分区：
文献类型：
--
作者：
Jain P;Nattakom M;Holowka D;Wang DH;Thomas Brenna J;Ku AT;Nguyen H;Ibrahim SF;Tumbar T
脂类代谢在上皮干细胞(SC)功能和癌变中的作用尚不清楚。已知转录因子RUNX1在体内调节小鼠上皮毛囊(HF)干细胞的增殖，并在几种鼠和人上皮癌中调节增殖。我们在体内发现了一个与脂质代谢相关的新的RUNX1 HFSC靶基因亚集，并证明了由RUNX1驱动的不同类别脂类的变化。抑制脂酶SCD1和Soat1活性协同减少小鼠皮肤上皮细胞以及人皮肤和口腔鳞状细胞癌培养株的增殖。我们的脂体分析显示，不同的RUNX1水平会导致皮肤单不饱和脂肪酸(如SCD1的产物油酸)的变化。此外，不同的RUNX1水平、SCD1的抑制或SCD1产物油酸的添加，分别影响小鼠角质形成细胞的质膜组织(或流动性)。这些因素还影响Wnt膜信号转导的强度，Wnt是一种促进上皮(癌症)细胞增殖和HFSC激活的途径。我们的工作模型是，HFSC因子RUNX1调节脂肪酸的产生，从而影响膜组织，促进正常和癌细胞上皮细胞的快速增殖的信号转导。
The role of lipid metabolism in epithelial stem cell (SC) function and carcinogenesis is poorly understood. The transcription factor Runx1 is known to regulate proliferation in mouse epithelial hair follicle (HF) SCs in vivo and in several mouse and human epithelial cancers. We found a novel sub-set of in vivo Runx1 HFSC target genes related to lipid metabolism and demonstrated changes in distinct classes of lipids driven by Runx1. Inhibition of lipid-enzymes Scd1 and Soat1 activity synergistically reduces proliferation of mouse skin epithelial cells and of human skin and oral squamous cell carcinoma cultured lines. Varying Runx1 levels induces changes in skin monounsaturated fatty acids (e.g. oleate, a product of Scd1) as shown by our lipidome analysis. Furthermore, varying Runx1 levels, the inhibition of Scd1, or the addition of Scd1-product oleate, individually affects the plasma membrane organization (or fluidity) in mouse keratinocytes. These factors also affect the strength of signal transduction through the membranes for Wnt, a pathway that promotes epithelial (cancer) cell proliferation and HFSC activation. Our working model is that HFSC factor Runx1 modulates the fatty acid production, which affects membrane organization, facilitating signal transduction for rapid proliferation of normal and cancer epithelial cells.
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影响因子：
--
作者：
Huang J;Fan XX;He J;Pan H;Li RZ;Huang L;Jiang Z;Yao XJ;Liu L;Leung EL;He JX
通讯作者：
He JX
影响因子：
5.2
作者：
Igal RA
通讯作者：
Igal RA
影响因子：
3.8
作者：
Kim, Seung-Jin;Choi, Hojung;Kim, Eungseok
通讯作者：
Kim, Eungseok
影响因子：
7.3
作者：
Lee, Jayhun;Tumbar, Tudorita
通讯作者：
Tumbar, Tudorita
影响因子：
23.9
作者：
Hamilton, Laura K.;Dufresne, Martin;Fernandes, Karl J. L.
通讯作者：
Fernandes, Karl J. L.