Role of Krüppel-Like Factor 4 in the Maintenance of Chemoresistance of Anaplastic Thyroid Cancer. Lee Su In,Kim Dae Kyoung,Seo Eun Jin,Choi Eun Jung,Kwon Yang Woo,Jang Il Ho,Lee Jin Choon,Kim Hyun Yul,Shong Minho,Kim Jae Ho,Kim Seong-Jang Thyroid : official journal of the American Thyroid Association BACKGROUND:Anaplastic thyroid cancer (ATC) has a very poor prognosis due to its aggressive nature and resistance to conventional treatment. Radiotherapy and chemotherapy are not fully effective because of the undifferentiated phenotype and enhanced drug resistance of ATC. The objective of this study was to evaluate the involvement of Krüppel-like factor 4 (KLF4), a stemness-associated transcription factor, in the undifferentiated phenotype and drug resistance of ATC. METHODS:ATC cells were compared to papillary thyroid cancer cells in drug resistance and gene expression. The effects of KLF4 knockdown in ATC cells on in vitro and in vivo drug resistance were measured. The effects of KLF4 overexpression and knockdown on ABC transporter activity were determined. RESULTS:ATC cells, such as HTH83, 8505C, and SW1736, exhibited higher resistance to the anticancer drug paclitaxel and higher expression of KLF4 than TPC-1 papillary thyroid cancer cells. Knockdown of KLF4 expression in ATC cells increased the expression of the thyroid-specific differentiation genes, such as thyrotropin receptor, thyroid peroxidase, thyroglobulin, and sodium-iodide symporter. Knockdown of KLF4 expression in ATC cells decreased the resistance to doxorubicin and paclitaxel, and reduced ABC transporter expression. Luciferase reporter assay results showed that KLF4 overexpression increased ABCG2 promoter activity, which was abolished by KLF4 knockdown. A tumorigenicity assay showed that the combination of paclitaxel treatment and KLF4 knockdown significantly decreased tumor mass originated from HTH83 cells in mice. CONCLUSIONS:ATC cells show high expression of KLF4, and KLF4 expression is necessary for maintaining the undifferentiated phenotype and drug resistance in vitro and in vivo. The present study identifies KLF4 as a potential therapeutic target for eliminating ATC cells. 10.1089/thy.2016.0414

Transcriptional regulation of macrophage cholesterol efflux and atherogenesis by a long noncoding RNA. Sallam Tamer,Jones Marius,Thomas Brandon J,Wu Xiaohui,Gilliland Thomas,Qian Kevin,Eskin Ascia,Casero David,Zhang Zhengyi,Sandhu Jaspreet,Salisbury David,Rajbhandari Prashant,Civelek Mete,Hong Cynthia,Ito Ayaka,Liu Xin,Daniel Bence,Lusis Aldons J,Whitelegge Julian,Nagy Laszlo,Castrillo Antonio,Smale Stephen,Tontonoz Peter Nature medicine Nuclear receptors regulate gene expression in response to environmental cues, but the molecular events governing the cell type specificity of nuclear receptors remain poorly understood. Here we outline a role for a long noncoding RNA (lncRNA) in modulating the cell type-specific actions of liver X receptors (LXRs), sterol-activated nuclear receptors that regulate the expression of genes involved in cholesterol homeostasis and that have been causally linked to the pathogenesis of atherosclerosis. We identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the gene Abca1, which is critical for regulation of cholesterol efflux. Mice lacking the MeXis gene show reduced Abca1 expression in a tissue-selective manner. Furthermore, loss of MeXis in mouse bone marrow cells alters chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Mechanistic studies reveal that MeXis interacts with and guides promoter binding of the transcriptional coactivator DDX17. The identification of MeXis as a lncRNA modulator of LXR-dependent gene expression expands understanding of the mechanisms underlying cell type-selective actions of nuclear receptors in physiology and disease. 10.1038/nm.4479

Krüppel-Like Factor 4 Regulation of Cholesterol-25-Hydroxylase and Liver X Receptor Mitigates Atherosclerosis Susceptibility. Li Zhao,Martin Marcy,Zhang Jin,Huang Hsi-Yuan,Bai Liang,Zhang Jiao,Kang Jian,He Ming,Li Jie,Maurya Mano R,Gupta Shakti,Zhou Guangjin,Sangwung Panjamaporn,Xu Yong-Jiang,Lei Ting,Huang Hsien-Da,Jain Mohit,Jain Mukesh K,Subramaniam Shankar,Shyy John Y-J Circulation BACKGROUND:Atherosclerosis is a multifaceted inflammatory disease involving cells in the vascular wall (eg, endothelial cells [ECs]), as well as circulating and resident immunogenic cells (eg, monocytes/macrophages). Acting as a ligand for liver X receptor (LXR), but an inhibitor of SREBP2 (sterol regulatory element-binding protein 2), 25-hydroxycholesterol, and its catalyzing enzyme cholesterol-25-hydroxylase (Ch25h) are important in regulating cellular inflammatory status and cholesterol biosynthesis in both ECs and monocytes/macrophages. METHODS:Bioinformatic analyses were used to investigate RNA-sequencing data to identify cholesterol oxidation and efflux genes regulated by Krüppel-like factor 4 (KLF4). In vitro experiments involving cultured ECs and macrophages and in vivo methods involving mice with Ch25h ablation were then used to explore the atheroprotective role of KLF4-Ch25h/LXR. RESULTS:Vasoprotective stimuli increased the expression of Ch25h and LXR via KLF4. The KLF4-Ch25h/LXR homeostatic axis functions through suppressing inflammation, evidenced by the reduction of inflammasome activity in ECs and the promotion of M1 to M2 phenotypic transition in macrophages. The increased atherosclerosis in apolipoprotein E/Ch25h mice further demonstrates the beneficial role of the KLF4-Ch25h/LXR axis in vascular function and disease. CONCLUSIONS:KLF4 transactivates Ch25h and LXR, thereby promoting the synergistic effects between ECs and macrophages to protect against atherosclerosis susceptibility. 10.1161/CIRCULATIONAHA.117.027462