The IL-36 subfamily of cytokines belongs to the IL-1 superfamily and consists of three pro-inflammatory agonists IL-36α, IL-36β, IL-36γ, and an IL-36 receptor (IL-36R) antagonist, IL-36Ra. These IL-36 cytokines function through a common receptor to modulate innate and adaptive immune responses. IL-36 cytokines are expressed as inactive precursors and require proteolytic processing to become fully active. Upon binding to IL-36R, IL-36 agonists augment the expression and production of inflammatory cytokines via activating signaling pathways. IL-36 is mainly expressed in epidermal, bronchial, and intestinal epithelial cells that form the barrier structures of the body and regulates the balance between pro-inflammatory and anti-inflammatory cytokine production at these tissue sites. Dysregulation of IL-36 signaling is a major etiological factor in the development of autoimmune and inflammatory diseases. Besides its critical role in inflammatory skin diseases such as psoriasis, emerging evidence suggests that aberrant IL-36 activities also promote inflammatory diseases in the lung, kidneys, and intestines, underscoring the potential of IL-36 as a therapeutic target for common inflammatory diseases. The role of IL-36 signaling in cancer development is also under investigation, with limited studies suggesting a potential anti-tumor effect. In this comprehensive review, we summarize current knowledge regarding the expression, activation, regulatory mechanisms, and biological functions of IL-36 signaling in immunity, inflammatory diseases, and cancer development.

The rates of melanoma and non‐melanoma skin cancer (NMSC) have been increasing over the last twenty years in the United States, and this has been attributed to increased ultraviolet radiation exposure (UVR). Given these rising rates, preventative measures have become increasingly important to reduce the incidence and promote early detection of these cancers. Skin cancer prevention remains a challenging task to accomplish mainly due to the lack of reliable and sensitive methods to provide objective risk information that can educate and motivate individuals to avoid sunburn. Currently, minimal erythema dose (MED) is used as a marker of UVR. However, it is not an ideal marker because significant cancer‐related molecular damage can occur after UVR exposure that cannot be detected by MED. Thus, over the recent years there has been significant interest in development of biomarkers indicative of exposure to UVR to improve early detection of cutaneous malignancies. Here, we will discuss emerging biomarkers for melanoma and NMSC that can help with risk stratification and targeted prevention and treatment.

Canonical ultraviolet (UV) mutation type and spectra are traditionally defined by direct sequencing-based approaches to map mutations in a limited number of representative DNA elements. To obtain an unbiased view of genome wide UV mutation features, we performed whole exome-sequencing (WES) to profile single nucleotide substitutions in UVB-irradiated primary human keratinocytes. Cross comparison of UV mutation profiles under different UVB radiation conditions revealed that T > C transition was highly prevalent in addition to C > T transition. We also identified 5′-ACG-3′ as a common sequence motif of C > T transition. Furthermore, our analyses uncovered several recurring UV mutations following acute UVB radiation affecting multiple genes including HRNR, TRIOBP, KCNJ12, and KMT2C, which are frequently mutated in skin cancers, indicating their potential role as founding mutations in UV-induced skin tumorigenesis. Pretreatment with trichostatin A, a pan-histone deacetylase inhibitor that renders chromatin decondensation, significantly decreased the number of mutations in UVB-irradiated keratinocytes. Unexpectedly, we found trichostatin A to be a mutagen that caused DNA damage and mutagenesis at least partly through increased reactive oxidation. In summary, our study reveals new UV mutation features following acute UVB radiation and identifies novel UV mutation hotspots that may potentially represent founding driver mutations in skin cancer development.

Breast cancer is a highly heterogeneous disease, encompassing many subtypes that have distinct origins, behaviors, and prognoses. Although traditionally seen as a genetic disease, breast cancer is now also known to involve epigenetic abnormalities. Epigenetic regulators, such as DNA methyltransferases and histone-modifying enzymes, play essential roles in gene regulation and cancer development. Dysregulation of epigenetic regulator activity has been causally linked with breast cancer pathogenesis. Hairless (HR) encodes a 130-kDa transcription factor that is essential for development and tissue homeostasis. Its role in transcription regulation is partly mediated by its interaction with multiple nuclear receptors, including thyroid hormone receptor, retinoic acid receptor-related orphan receptors, and vitamin D receptor. HR has been studied primarily in epidermal development and homeostasis. Hr-mutant mice are highly susceptible to ultraviolet- or carcinogen-induced skin tumors. Besides its putative tumor suppressor function in skin, loss of HR function has also been implicated in increased leukemia susceptibility and promotes the growth of melanoma and brain cancer cells. HR has also been demonstrated to function as a histone H3 lysine 9 demethylase. Recent genomics studies have identified HR mutations in a variety of human cancers, including breast cancer. The anticancer function and mechanism of action by HR in mammary tissue remains to be investigated. Here, we review the emerging role of HR, its histone demethylase activity and histone methylation in breast cancer development, and potential for epigenetic therapy.

Currently, there is no sensitive molecular test for identifying transformation‐prone actinic keratoses (AKs) and aggressive squamous cell carcinoma (SCC) subtypes. Biomarker‐based molecular testing represents a promising tool for risk stratifying these lesions. We evaluated the utility of a panel of ultraviolet (UV) radiation‐biomarker genes in distinguishing between benign and transformation‐prone AKs and SCCs. The expression of the UV‐biomarker genes in 31 SCC and normal skin (NS) pairs and 10 AK/NS pairs was quantified using the NanoString nCounter system. Biomarker testing models were built using logistic regression models with leave‐one‐out cross validation in the training set. The best model to classify AKs versus SCCs (area under curve (AUC) 0.814, precision score 0.833, recall 0.714) was constructed using a top‐ranked set of 13 UV‐biomarker genes. Another model based on a 15‐gene panel was developed to differentiate histologically concerning from less concerning SCCs (AUC 1, precision score 1, recall 0.714). Finally, 12 of the UV‐biomarker genes were differentially expressed between AKs and SCCs, while 10 genes were uniquely expressed in the more concerning SCCs. UV‐biomarker gene subsets demonstrate dynamic utility as molecular tools to classify and risk stratify AK and SCC lesions, which will complement histopathologic diagnosis to guide treatment of high‐risk patients.