The research has revealed more about the complexities of skin ageing and the importance of p53 mutations in regulating hyaluronic acid synthesis in keratinocytes. This, in turn, could aid the development of skin care/dermatology products and sunscreen formulations that protect against UV exposure in human keratinocytes and for melanoma cancer.
“The findings advance our understanding of cancer research, particularly melanoma cancer that originates in melanocytes attached to keratinocytes in the epidermis,” explained lead researcher Dr Kaustuv Basu, who worked with PI Dr Paraskevi Heldin and a team of researchers on the study.
“Keratinocytes play a significant role in melanoma’s initiation, progression, and spread,” he continued. “This knowledge is paramount in strategising dermatology products for melanoma cancer.”
The research, which was conducted at the Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden was supported by grants from the Swedish Cancer Society and has been published in the journal ‘Proteoglycan Research’.
The study into the complex regulation of hyaluronan synthesis in keratinocytes (the primary skin cells in the epidermis) could also “pave the way for new insights into and potential manipulation of keratinocyte behaviour,” according to the researchers.
Hyaluronic acid and skin health
Hyaluronic acid is essential for skin health and produced by hyaluronan synthases (HAS), which are encoded by the HAS1, HAS2, and HAS3 genes. In keratinocytes, HAS2 and HAS3 synthesise hyaluronic acid of varying molecular weights. Their activity is regulated by growth factors like transforming growth factor-β1 (TGF-β1)2 and transcription factors such as p53 and p63.
“Hyaluronic acid, p53, and TGF-β1 are critical for keratinocyte growth, migration, and differentiation, yet their interactions were not fully understood,” explained Basu.
“p53 plays a vital role in apoptosis regulation and affects skin thickness, hair growth, wound repair, and sebaceous gland secretion. As a tumour suppressor, it is the most frequently mutated gene in human cancers,” he continued.
“Conversely, p63, a paralogue of p53, is crucial for the development and function of keratinocytes, particularly through its isoform ΔNp63, which supports hyaluronic acid metabolism.”
Basu continued to explain that p63 and p53 often oppose each other in function and that the RAS (renin–angiotensin system) is also key to processes like cell cycle regulation and stress responses.
“Hyaluronic acid activates mitogen-activated protein kinase through the RAS-signalling pathway, underscoring its role in skin health,” he explained.
“In the HaCaT keratinocyte cell line, which expresses mutant p53, ΔNp63 binds to the genomic loci of HAS2 and HAS3, with an increased binding to HAS2 due to RAS activation and TGF-β1 suppression of p53,” he shared.
“However, there was no clue how the balance between p53 and p63 controlled the transcription of HAS isoforms, with potential implications for improving skin health.”
Key findings of the research
This new research has discovered that p53 suppresses the expression of HAS2 and HAS3 mRNA and reduces the synthesis of extracellular hyaluronic acid in HaCaT keratinocytes.
While, in contrast, ΔNp63 enhances the expression of HAS2 and HAS3 mRNA4.
“Eliminating p53 leads to an increase in HAS2 and HAS3 expression and extracellular hyaluronic acid synthesis,” explained Basu.
“Notably, we have observed that the p53 mutation variably affects extracellular hyaluronic acid synthesis.”
The research team proposes that hyaluronic acid synthesis depends not only on the status of p53, but also on the cellular context, which plays a significant role in its regulation.
“TGF-β1 stimulation increases the levels of HAS2 and HAS3,” Basu continued. “However, when mutant p53 is eliminated in the presence of TGF-β1 stimulation, there is a marked difference in HAS2 and HAS3 mRNA expression (the HAS2 levels increase while HAS3 levels decrease).
Basu said this research showed “that RAS and TGF-β1 synergistically activate HAS2 and CD44, but not HAS3.”
“This suggests that the status of p53, along with the transcriptional programs of p53 and ΔNp63 in skin epithelial cells, may differently impact the length of hyaluronic acid, potentially affecting skin health,” he continued.
This understanding could lead to new insights into keratinocyte behaviour for skin care formulators and open up new avenues for R&D.
The impact on skin care R&D
As the effectiveness of skincare and dermatology products depend on the ability of the ingredients to penetrate the skin layers and nourish the cells, Basu noted that understanding the cell signalling mechanisms that regulate skin health is essential, as the active ingredients can significantly impact these processes.
Hyaluronic acid, collagen, and elastin are all key components of the skin. Hyaluronic acid, a large sugar molecule, is vital for skin hydration, while collagen and elastin are proteins that provide structural support and elasticity.
Hyaluronic acid is produced by hyaluronan synthases in various molecular weights. High molecular weight hyaluronic acid offers protective benefits, such as preventing inflammation and cancer, while low molecular weight hyaluronic acid can be detrimental, potentially triggering inflammation and cancer.
“Once produced, hyaluronic acid binds to receptors such as CD44, which regulates collagen and elastin production. This makes hyaluronic acid and its signalling molecules crucial for maintaining skin physiology and structural integrity,” explained Basu.
The gradual loss of hyaluronic acid in the skin, particularly in the epidermis leads to wrinkles as we age. This is why many skin care formulations feature hyaluronic acid.
“Selecting enhancers or inhibitors of hyaluronan synthase regulators is key to formulating effective skincare products. Understanding the complex regulation mechanisms of hyaluronic acid synthesis and identifying the molecules that affect hyaluronan synthases in the skin are essential for improving skincare and dermatology products,” Basu concluded.
Source
Proteoglycan Research Volume3, Issue 1 (January-March 2025) “p53 and ΔNp63 Transcriptional Programs in Coordination With TGF-β1 and RAS Activation Regulate HAS2 and HAS3 in Epithelial Cells”
https://onlinelibrary.wiley.com/doi/10.1002/pgr2.70015
Authors: Kaustuv Basu | Yanshuang Li | Arianna Parnigoni | Eleftheria Vasilaki | Constantinos Kolliopoulos | Paraskevi Heldin
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
Funding: Supported by grants from the Swedish Cancer Society (180657).