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

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, whereas knockdown inhibited proliferation and increased the rate of differentiation. Furthermore, we found that PFKFB3 was highly expressed in psoriatic epidermis. Our results show that PFKFB3 is a key regulator of epidermal homeostasis and may represent a therapeutic target for epidermal diseases associated with hyperproliferation and impaired differentiation.