Transcription Factor CTIP1/ BCL11A Regulates Epidermal Differentiation and Lipid Metabolism During Skin Development

The skin protects the human body against dehydration and harmful challenges. Keratinocytes (KCs) are the most abundant epidermal cells, and it is anticipated that KC-mediated transport of Na+ ions creates a physiological barrier of high osmolality against the external environment. Here, we studied the role of NFAT5, a transcription factor whose activity is controlled by osmotic stress in KCs. Cultured KCs from adult mice were found to secrete more than 300 proteins, and upon NFAT5 ablation, the secretion of several matrix proteinases, including metalloproteinase-3 (Mmp3) and kallikrein-related peptidase 7 (Klk7), was markedly enhanced. An increase in Mmp3 and Klk7 RNA levels was also detected in transcriptomes of Nfat5-/- KCs, along with increases of numerous members of the ‘Epidermal Differentiation Complex’ (EDC), such as small proline-rich (Sprr) and S100 proteins. NFAT5 and Mmp3 as well as NFAT5 and Klk7 are co-expressed in the basal KCs of fetal and adult epidermis but not in basal KCs of newborn (NB) mice. The poor NFAT5 expression in NB KCs is correlated with a strong increase in Mmp3 and Klk7 expression in KCs of NB mice. These data suggests that, along with the fragile epidermis of adult Nfat5-/- mice, NFAT5 keeps in check the expression of matrix proteases in epidermis. The NFAT5-mediated control of matrix proteases in epidermis contributes to the manifold changes in skin development in embryos before and during birth, and to the integrity of epidermis in adults.

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Transcription Factor Ctip2 Controls Epidermal Lipid Metabolism and Regulates Expression of Genes Involved in Sphingolipid Biosynthesis during Skin Development

Journal of Investigative Dermatology ◽

10.1038/jid.2012.358 ◽

2013 ◽

Vol 133 (3) ◽

pp. 668-676 ◽

Cited By ~ 17

Author(s):

Zhixing Wang ◽

Jay S. Kirkwood ◽

Alan W. Taylor ◽

Jan F. Stevens ◽

Mark Leid ◽

...

Keyword(s):

Transcription Factor ◽

Lipid Metabolism ◽

Skin Development ◽

Expression Of Genes ◽

Sphingolipid Biosynthesis

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All Roads Go to the Nucleus: Integration of Signaling/Transcription Factor-Mediated and Epigenetic Regulatory Mechanisms in the Control of Skin Development and Regeneration

Stem Cell Biology and Regenerative Medicine - Epigenetic Regulation of Skin Development and Regeneration ◽

10.1007/978-3-319-16769-5_1 ◽

2018 ◽

pp. 1-55

Author(s):

Vladimir A. Botchkarev ◽

Andrey A. Sharov ◽

Michael Y. Fessing

Keyword(s):

Transcription Factor ◽

Regulatory Mechanisms ◽

Skin Development

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How cancer cells remodel lipid metabolism: strategies targeting transcription factors

Lipids in Health and Disease ◽

10.1186/s12944-021-01593-8 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Do-Won Jeong ◽

Seulbee Lee ◽

Yang-Sook Chun

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Lipid Metabolism ◽

Cancer Cells ◽

Cancer Biology ◽

Factors Associated ◽

Modeling Techniques ◽

Related Enzyme ◽

Potential Strategy

AbstractReprogramming of lipid metabolism has received increasing recognition as a hallmark of cancer cells because lipid dysregulation and the alteration of related enzyme profiles are closely correlated with oncogenic signals and malignant phenotypes, such as metastasis and therapeutic resistance. In this review, we describe recent findings that support the importance of lipids, as well as the transcription factors involved in cancer lipid metabolism. With recent advances in transcription factor analysis, including computer-modeling techniques, transcription factors are emerging as central players in cancer biology. Considering the limited number and the crucial role of transcription factors associated with lipid rewiring in cancers, transcription factor targeting is a promising potential strategy for cancer therapy.

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Homeobox transcription factor DLX4 is not necessary for skin development and homeostasis

Experimental Dermatology ◽

10.1111/exd.13503 ◽

2018 ◽

Vol 27 (3) ◽

pp. 289-292 ◽

Cited By ~ 1

Author(s):

Shreya Bhattacharya ◽

Olivier Duverger ◽

Stephen R. Brooks ◽

Maria I. Morasso

Keyword(s):

Transcription Factor ◽

Skin Development ◽

Homeobox Transcription Factor

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Lipid metabolism enzyme 5-LOX and its metabolite LTB4 are capable of activating transcription factor NF-κB in hepatoma cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2012.01.068 ◽

2012 ◽

Vol 418 (4) ◽

pp. 647-651 ◽

Cited By ~ 12

Author(s):

Yu Zhao ◽

Wenhui Wang ◽

Qi Wang ◽

Xiaodong Zhang ◽

Lihong Ye

Keyword(s):

Transcription Factor ◽

Lipid Metabolism ◽

Hepatoma Cells ◽

Metabolism Enzyme ◽

Activating Transcription Factor

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Overexpression of the Epidermis-Specific Homeodomain-Leucine Zipper IV Transcription Factor OUTER CELL LAYER1 in Maize Identifies Target Genes Involved in Lipid Metabolism and Cuticle Biosynthesis

PLANT PHYSIOLOGY ◽

10.1104/pp.109.150540 ◽

2010 ◽

Vol 154 (1) ◽

pp. 273-286 ◽

Cited By ~ 59

Author(s):

Marie Javelle ◽

Vanessa Vernoud ◽

Nathalie Depège-Fargeix ◽

Christine Arnould ◽

Delphine Oursel ◽

...

Keyword(s):

Transcription Factor ◽

Lipid Metabolism ◽

Leucine Zipper ◽

Target Genes ◽

Outer Cell

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AP1 Transcription Factors in Epidermal Differentiation and Skin Cancer

Journal of Skin Cancer ◽

10.1155/2013/537028 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 34

Author(s):

Richard L. Eckert ◽

Gautam Adhikary ◽

Christina A. Young ◽

Ralph Jans ◽

James F. Crish ◽

...

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Dominant Negative ◽

Epidermal Differentiation ◽

Cancer Development ◽

Multiple Cells ◽

Different Levels ◽

Factor Function

AP1 (jun/fos) transcription factors (c-jun, junB, junD, c-fos, FosB, Fra-1, and Fra-2) are key regulators of epidermal keratinocyte survival and differentiation and important drivers of cancer development. Understanding the role of these factors in epidermis is complicated by the fact that each protein is expressed, at different levels, in multiple cells layers in differentiating epidermis, and because AP1 transcription factors regulate competing processes (i.e., proliferation, apoptosis, and differentiation). Variousin vivogenetic approaches have been used to study these proteins including targeted and conditional knockdown, overexpression, and expression of dominant-negative inactivating AP1 transcription factors in epidermis. Taken together, these studies suggest that individual AP1 transcription factors have different functions in the epidermis and in cancer development and that altering AP1 transcription factor function in the basal versus suprabasal layers differentially influences the epidermal differentiation response and disease and cancer development.

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Interplay and cooperation between SREBF1 and master transcription factors regulate lipid metabolism and tumor-promoting pathways in squamous cancer

Nature Communications ◽

10.1038/s41467-021-24656-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Li-Yan Li ◽

Qian Yang ◽

Yan-Yi Jiang ◽

Wei Yang ◽

Yuan Jiang ◽

...

Keyword(s):

Transcription Factor ◽

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Human Cancer ◽

Regulatory Element ◽

Regulatory Elements ◽

Gene Set Enrichment Analysis ◽

Transcriptional Dysregulation

AbstractSquamous cell carcinomas (SCCs) comprise one of the most common histologic types of human cancer. Transcriptional dysregulation of SCC cells is orchestrated by tumor protein p63 (TP63), a master transcription factor (TF) and a well-researched SCC-specific oncogene. In the present study, both Gene Set Enrichment Analysis (GSEA) of SCC patient samples and in vitro loss-of-function assays establish fatty-acid metabolism as a key pathway downstream of TP63. Further studies identify sterol regulatory element binding transcription factor 1 (SREBF1) as a central mediator linking TP63 with fatty-acid metabolism, which regulates the biosynthesis of fatty-acids, sphingolipids (SL), and glycerophospholipids (GPL), as revealed by liquid chromatography tandem mass spectrometry (LC-MS/MS)-based lipidomics. Moreover, a feedback co-regulatory loop consisting of SREBF1/TP63/Kruppel like factor 5 (KLF5) is identified, which promotes overexpression of all three TFs in SCCs. Downstream of SREBF1, a non-canonical, SCC-specific function is elucidated: SREBF1 cooperates with TP63/KLF5 to regulate hundreds of cis-regulatory elements across the SCC epigenome, which converge on activating cancer-promoting pathways. Indeed, SREBF1 is essential for SCC viability and migration, and its overexpression is associated with poor survival in SCC patients. Taken together, these data shed light on mechanisms of transcriptional dysregulation in cancer, identify specific epigenetic regulators of lipid metabolism, and uncover SREBF1 as a potential therapeutic target and prognostic marker in SCC.

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