Potential Tumor Suppressor Role of Polo-like Kinase 5 in Cancer.

The polo-like kinase (PLK) family of serine/threonine kinases contains five members (PLK1-5). Most PLKs are involved in cell cycle regulation and DNA damage response. However, PLK5 is different as it lacks a functional kinase domain and is not involved in cell cycle control. PLK5 remains the least-studied family member, and its role in oncogenesis remains enigmatic. Here, we identified tissues with high PLK5 expression by leveraging the Protein Atlas and GTEx databases with relevant literature and selected ovarian, lung, testis, endometrium, cervix, and fallopian tube tissues as candidates for further investigation. Subsequently, we performed immunohistochemical staining for PLK5 on multiple tissue microarrays followed by Vectra scanning and quantitative inForm analysis. This revealed consistently downregulated PLK5 expression in these cancers compared to normal tissues. To validate and extend our findings, we performed pan-cancer analysis of PLK5 expression using public RNAseq databases (TCGA and GTEx). We found PLK5 is downregulated in 18 cancer types, including our selected candidates. Interestingly, we also observed PLK5 expression remains consistently low in later stages of cancer, suggesting PLK5 may have a greater role in tumor initiation than cancer progression. Overall, our study demonstrates PLK5 downregulation in multiple cancers, highlighting its role as a tumor suppressor.

Mechanisms of Immunotherapy Resistance in Cutaneous Melanoma: Recognizing a Shapeshifter.

Melanoma is one of the seven most common cancers in the United States, and its incidence is still increasing. Since 2011, developments in targeted therapies and immunotherapies have been essential for significantly improving overall survival rates. Prior to the advent of targeted and immunotherapies, metastatic melanoma was considered a death sentence, with less than 5% of patients surviving more than 5 years. With the implementation of immunotherapies, approximately half of patients with metastatic melanoma now survive more than 5 years. Unfortunately, this also means that half of the patients with melanoma do not respond to current therapies and live less than 5 years after diagnosis. One major factor that contributes to lower response in this population is acquired or primary resistance to immunotherapies via tumor immune evasion. To improve the overall survival of melanoma patients new treatment strategies must be designed to minimize the risk of acquired resistance and overcome existing primary resistance. In recent years, many advances have been made in identifying and understanding the pathways that contribute to tumor immune evasion throughout the course of immunotherapy treatment. In addition, results from clinical trials focusing on treating patients with immunotherapy-resistant melanoma have reported some initial findings. In this review, we summarize important mechanisms that drive resistance to immunotherapies in patients with cutaneous melanoma. We have focused on tumor intrinsic characteristics of resistance, altered immune function, and systemic factors that contribute to immunotherapy resistance in melanoma. Exploring these pathways will hopefully yield novel strategies to prevent acquired resistance and overcome existing resistance to immunotherapy treatment in patients with cutaneous melanoma.

Antimelanoma Effects of Concomitant Inhibition of SIRT1 and SIRT3 in BrafV600E/PtenNULL Mice.

Novel therapeutic strategies are required for the effective and lasting treatment of metastatic melanoma, one of the deadliest skin malignancies. In this study, we determined the antimelanoma efficacy of 4'-bromo-resveratrol (4'-BR), which is a small-molecule dual inhibitor of SIRT1 and SIRT3, in a BrafV600E/PtenNULL mouse model that recapitulates human disease, including metastases. Tumors were induced by topical application of 4-hydroxy-tamoxifen on shaved backs of mice aged 10 weeks, and the effects of 4'-BR (5‒30 mg/kg of body weight, intraperitoneally, 3 days per week for 5 weeks) were assessed on melanoma development and progression. We found that 4'-BR at a dose of 30 mg/kg significantly reduced the size and volume of primary melanoma tumors as well as lung metastasis with no adverse effects. Furthermore, mechanistic studies on tumors showed significant modulation in the markers of proliferation, survival, and melanoma progression. Because SIRT1 and SIRT3 are linked to immunomodulation, we performed differential gene expression analysis using a PanCancer Immune Profiling Panel (770 genes). Our data showed that 4'-BR significantly downregulated the genes related to metastasis promotion, chemokine/cytokine regulation, and innate/adaptive immune functions. Overall, inhibition of SIRT1 and SIRT3 by 4'-BR is a promising antimelanoma therapy with antimetastatic and immunomodulatory activities warranting further detailed studies, including clinical investigations.

CRISPR/Cas9-mediated Knockout of SIRT6 Imparts Remarkable Antiproliferative Response in Human Melanoma Cells in vitro and in vivo.

Melanoma is one of the most aggressive, potentially fatal forms of skin cancer and has been shown to be associated with solar ultraviolet radiation-dependent initiation and progression. Despite remarkable recent advances with targeted and immune therapeutics, lasting and recurrence-free survival remain significant concerns. Therefore, additional novel mechanism-based approaches are needed for effective melanoma management. The sirtuin SIRT6 appears to have a pro-proliferative function in melanocytic cells. In this study, we determined the effects of genetic manipulation of SIRT6 in human melanoma cells, in vitro and in vivo. Our data demonstrated that CRISPR/Cas9-mediated knockout (KO) of SIRT6 in A375 melanoma cells resulted in a significant (1) decrease in growth, viability and clonogenic survival and (2) induction of G1-phase cell cycle arrest. Further, employing a RT2 Profiler PCR array containing 84 key transformation and tumorigenesis genes, we found that SIRT6 KO resulted in modulation of genes involved in angiogenesis, apoptosis, cellular senescence, epithelial-to-mesenchymal transition, hypoxia signaling and telomere maintenance. Finally, we found significantly decreased tumorigenicity of SIRT6 KO A375 cells in athymic nude mice. Our data provide strong evidence that SIRT6 promotes melanoma cell survival, both in vitro and in vivo, and could be exploited as a target for melanoma management.

The sirtuin 6: An overture in skin cancer.

In the recent past, the sirtuins have been under intense investigation for their roles in biology and disease, including cancer. The sirtuin SIRT6 is comparatively a lesser studied member of this family of seven proteins. Like certain other sirtuins, SIRT6 is emerging to have an oncogenic function as well as tumor suppressor roles in cancer. Limited studies have been conducted assessing the role and functional significance of SIRT6 in melanoma and non-melanoma skin cancers. In this review, we have attempted to critically dissect the potential role and significance of SIRT6 in skin carcinogenesis. With limited available information to date, SIRT6 appears to have a pro-proliferative function in non-melanoma skin cancers (NMSCs), including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In addition, SIRT6 is also emerging to have an oncogenic function in melanoma. Moreover, we have provided information regarding the available SIRT6 inhibitors. Conclusively, it appears that additional comprehensive studies are needed to establish the role of SIRT6 in skin biology and skin diseases, including cancer. Further, concerted efforts are needed to characterize the stage-specific role of SIRT6 in skin cancers.