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

Abstract

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.

Host Response of Human Epidermis to Methicillin-Resistant Staphylococcus aureus Biofilm Infection and Synthetic Antibiofilm Peptide Treatment

“…This shifting in immune response is beneficial as prolonged inflammation and reactive oxygen species generated by bacterial infection often result in genomic instability. For example, S. aureus infections can trigger DNA damage and delay the cell cycle transition through induction of oxidative stress [ 64 , 65 ]. Skin cancer-associated S. aureus secretomes have also been shown to suppress DNA repair mechanisms including homologous recombination, mismatch, base excision, nucleotide excision, and double-strand break repair in keratinocytes [ 65 ].…”

“…For example, S. aureus infections can trigger DNA damage and delay the cell cycle transition through induction of oxidative stress [ 64 , 65 ]. Skin cancer-associated S. aureus secretomes have also been shown to suppress DNA repair mechanisms including homologous recombination, mismatch, base excision, nucleotide excision, and double-strand break repair in keratinocytes [ 65 ]. Here we reported a novel protective function of synthetic host defense peptide DJK-5 through upregulation of DNA repair mechanisms ( Figure 4 ).…”

Targeting Staphylococcus aureus dominated skin dysbiosis in actinic keratosis to prevent the onset of cutaneous squamous cell carcinoma: Outlook for future therapies?

“…Patients with AK lesions often present with Staphylococcus as the dominant taxon on the skin, and a high portion of this taxon are S. aureus. S. aureus secrete toxins on the skin which can cause human keratinocytes to overexpress inflammatory factors that may promote skin carcinogenesis (21)(22)(23)(24). While no causative relationship between S. aureus colonization and AK to cSCC progression has been established to date, this hypothesis presents an interesting interdisciplinary avenue to explore in the fields of oncology and microbiology.…”

“…Wood et al noted that Malassezia and Cutibacterium (previously known as Propionibacterium) are associated with non-lesional photodamaged skin, whereas S. aureus is associated with AK and cSCC lesions (19). A number of studies have suggested a link between the skin microbiota and cSCC progression, whereby S. aureus has been found in high relative abundance on AK lesions, but even more so on cSCCs (18,19,(21)(22)(23)(24)(25). The presence of pathogenic bacteria on the skin can cause an inflammatory response, and inflammation is widely recognized as a factor in tumorigenesis, discussed in more detail below (26).…”

Microbiota, probiotics and common skin cancer: Association and therapeutic application

“…Some studies, for example, have found a link between Staphylococcus aureus and squamous cell carcinoma (14). It has been demonstrated that the abundance of S. aureus in Squamous Skin Cancer (SSC) is significantly greater than in normal skin cells (15,16). Cutibacterium spp.…”