Skin Cancer-Associated S. aureus Strains Can Induce DNA Damage in Human Keratinocytes by Downregulating DNA Repair and Promoting Oxidative Stress.

Abstract

Simple SummarySquamous cell carcinoma of the skin and precancerous skin lesions, called actinic keratoses, on severely photodamaged skin are often colonized with unusually high amounts of the bacterium Staphylococcus aureus. It is not yet known whether this bacterium directly contributes to cancer formation in the skin. To test this, we exposed healthy human skin cells in culture to secreted compounds from S. aureus taken from precancerous and cancerous skin lesions. We then determined if the S. aureus-treated skin cells start showing typical signs of cancer transformation by looking at the changes in RNA transcripts and proteins. We found that the secreted compounds from some S. aureus strains were able to induce cancer-promoting changes in skin cells. Our findings suggest that S. aureus colonization on precancerous skin may contribute to cancer development and that there might be benefits of eradicating S. aureus on heavily photodamaged skin.Actinic keratosis (AK) is a premalignant lesion, common on severely photodamaged skin, that can progress over time to cutaneous squamous cell carcinoma (SCC). A high bacterial load of Staphylococcus aureus is associated with AK and SCC, but it is unknown whether this has a direct impact on skin cancer development. To determine whether S. aureus can have cancer-promoting effects on skin cells, we performed RNA sequencing and shotgun proteomics on primary human keratinocytes after challenge with sterile culture supernatant (‘secretome’) from four S. aureus clinical strains isolated from AK and SCC. Secretomes of two of the S. aureus strains induced keratinocytes to overexpress biomarkers associated with skin carcinogenesis and upregulated the expression of enzymes linked to reduced skin barrier function. Further, these strains induced oxidative stress markers and all secretomes downregulated DNA repair mechanisms. Subsequent experiments on an expanded set of lesion-associated S. aureus strains confirmed that exposure to their secretomes led to increased oxidative stress and DNA damage in primary human keratinocytes. A significant correlation between the concentration of S. aureus phenol soluble modulin toxins in secretome and the secretome-induced level of oxidative stress and genotoxicity in keratinocytes was observed. Taken together, these data demonstrate that secreted compounds from lesion-associated clinical isolates of S. aureus can have cancer-promoting effects in keratinocytes that may be relevant to skin oncogenesis.