PFKFB3, a Direct Target of p63, Is Required for Proliferation and Inhibits Differentiation in Epidermal Keratinocytes

Abstract

p63 is a transcription factor essential for epidermal development and homeostasis. p63 is a member of the p53 family of transcription factors, which are increasingly understood to be regulators of cellular metabolism. How p63 regulates metabolism in epidermal keratinocytes is incompletely understood, and it is unknown whether glycolytic regulation is essential to maintain the balance between proliferation and differentiation within the epidermis. We found that p63 promotes glycolytic metabolism in epidermal keratinocytes. p63 bound to consensus sites within the PFKFB3 gene and was required for PFKFB3 mRNA and protein expression. PFKFB3 overexpression inhibited differentiation of keratinocytes while knockdown inhibited proliferation and increased the rate of differentiation. Furthermore, we found that PFKFB3 was highly expressed in psoriatic epidermis. Our results reveal that PFKFB3 is a key regulator of epidermal homeostasis and may represent a therapeutic target for epidermal diseases associated with hyperproliferation and impaired differentiation.

AHR Regulates Metabolic Reprogramming to Promote SIRT1-Dependent Keratinocyte Differentiation

“…Glycolysis is an essential metabolic pathway that provides energy and reducing equivalents to sustain cell division. While the link between increased glycolysis and cell proliferation is widely supported, a link between decreased glycolysis and cell differentiation, particularly in epithelial cells, is emerging (Hamanaka and Mutlu, 2017;Kennedy et al, 2013). As reported previously, activation of the AHR not only increases many of the critical proteins and lipids involved in the differentiation of keratinocytes, but also diminishes the glycolytic and mitochondrial functions of these cells and increases mitochondrial reactive oxygen species.…”

“…Their expression decreases during calcium-induced differentiation. Furthermore, decreasing PFKFB3 by chemical or genetic means elevates the expression of differentiation markers and inhibits the proliferation of keratinocytes, while genetic expression of PFKFB3 opposes differentiation (Hamanaka and Mutlu, 2017).…”

Psoriatic Dermal-derived Mesenchymal Stem Cells Reduce Keratinocyte Junctions, and Increase Glycolysis

“…Glycolysis also plays an essential role in cell proliferation by maintaining high levels of glycolytic intermediates to support cellular anabolic reactions (28). Conversely, the decreased glycolysis is related to cell differentiation (29,30), particularly keratinocyte differentiation (27). Hence, increased KC proliferation in psoriasis could be attributable to DMSC-induced elevations in glycolysis.…”

FIH‐1 engages novel binding partners to positively influence epithelial proliferation via p63

“…Among them, ΔNp63α 1 is the main isoform in proliferating keratinocytes 2 and thought to be obligatory for proper development of epithelial structures. 6 Although much is known about the genes regulated by p63 in keratinocytes and the epidermis, [9][10][11] how p63 is regulated is less clear. 2,5 Furthermore, ΔNp63 prevents Notch signaling, which inhibits p21 expression, thereby retarding epidermal differentiation.…”