Expression profile of SIRT2 in human melanoma and implications for sirtuin-based chemotherapy

Abstract

Melanoma is cancer of melanin-containing melanocyte cells. This neoplasm is one of the most deadly forms of skin cancer, and currently available therapeutic options are insufficient in significantly improve outcomes for many patients. Therefore, novel targets are required to effectively manage this neoplasm. Several sirtuins have previously been found to be upregulated in melanoma, so in this study, the expression profile of SIRT2 was determined. Employing a tissue microarray containing benign nevi, primary melanomas, and lymph node metastases, we have found that the tissue from lymph node metastases appears to have a significant upregulation of SIRT2 relative to primary tumors across the nuclear, cytoplasmic, and whole cell data. Additionally, SIRT2 staining was found to be higher in the nucleus of metastatic melanomas compared to cytoplasmic staining. As SIRT2 is considered to be a predominantly cytoplasmic protein, this is a novel and very interesting finding. This, combined with previous studies that show other sirtuins are increased in melanoma and involved in cellular proliferation and survival, leads to the suggestion that exploring pan-sirtuin inhibitors may be the best target for the next iteration of melanoma chemotherapeutics.

SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a

“…Thus SIRT2 may provide an additional link between K-Ras4a signaling and cellular metabolism. Given that Ras proteins play critical roles in many human cancers, SIRT2, as a Ras regulator, may be an important therapeutic target for cancer, which is consistent with several recent reports ( Jing et al, 2016 ; Moniot et al, 2017 ; Shah et al, 2016 ; Wang et al, 2014 ; Wilking-Busch et al, 2017 ; Xu et al, 2016 ; Zhao et al, 2013 , 2016 ). The physiological and pathophysiological roles of SIRT2 thus merit further investigation.…”

SIRT2 and lysine fatty acylation regulate the oncogenic activity of K-Ras4a

“…Thus SIRT2 may provide an additional link between K-Ras4a signaling and cellular metabolism. Given that Ras proteins play critical roles in many human cancers, SIRT2, as a Ras regulator, may be an important therapeutic target for cancer, which is consistent with several recent reports 50,53, 54,57,58,85–87 . The physiological and pathophysiological roles of SIRT2 thus merit further investigation.…”

SIRT6 histone deacetylase functions as a potential oncogene in human melanoma

“…For quantitative staining analysis, the Vectra automated quantitative tissue imaging system, including an automated slide scanner and state-of-the-art software (Nuance and inForm; PerkinElmer) was used, as described previously [ 8 ]. This system takes advantage of the unique spectral characteristics (curve) of each chromogen via creation of a spectral library from single-chromogen slides in order to determine the relative contribution of each chromogen to the stained area on a slide.…”