The Role Of Glucose Metabolism And Sirt6 In Skin Carcinogenesis

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Metabolic reprogramming to aerobic glycolysis, as described by Otto Warburg decades ago, has recently emerged as a key event during tumorigenesis. However, molecular details underlying this change are still under intense investigation, and how chromatin modulators might affect the metabolic profiles of cells remains largely unknown. Our lab has shown that the histone deacetylase sirtuin 6 (SIRT6) inhibits HIF-1- and c-Myc-dependent transcription, both of which are critical in metabolic reprogramming of cells (Zhong et al., Cell, 2010 & Sebastian et al., Cell, 2012). Lack of SIRT6 leads to enhance aerobic glycolysis and ribosome biogenesis, in turn promoting cancer initiation and growth. Skin is an attractive organ system to dissect multi-step carcinogenesis. Notably, despite a long history of skin cancer research, the role of metabolic reprogramming in skin carcinogenesis remains largely unexplored. In this research, I will address the hypothesis that loss of SIRT6 results in a metabolic switch toward aerobic glycolysis, facilitating tumor initiation or progression in skin. In preliminary studies, I found that knockdown of SIRT6 in JB6 P- mouse immortalized keratinocytes increased expression of key glycolytic enzymes such as LDH-a, PDK1, and GLUT1. Glucose uptake was elevated in the absence of SIRT6, and cells without SIRT6 proliferated faster than control cells. For in vivo studies, I generated mice lacking Sirt6 specifically in the skin epidermis (K14-cre) and treated these mice according to the DMBA/TPA skin tumorigenesis protocol. Strikingly, tumor onset in Sirt6fl/fl mice was faster than Sirt6+/+ mice. Further, the size of tumors at 14 weeks after DMBA treatment in the Sirt6fl/fl mice was clearly bigger than the ones in control animals. Using immunohistochemistry against PCNA as a proliferation marker or Glut1 as an indicator of glucose uptake in skin epidermis, I found that the tumors from Sirt6fl/fl mice showed more PCNA-positive layers compared to the tumors from Sirt6+/+ mice. Surprisingly, most of the Glut1+ cells were also PCNA+ in the DMBA/TPA-treated skin, implying that proliferating cells have an increased glucose metabolism. Such increase in glycolytic metabolism was in striking contrast to normal proliferating skin cells, where PCNA+ cells were readily detectable, but were negative for Glut1. These results support the idea that actively proliferating cells in tumors have a unique requirement for glycolytic metabolism. Our studies should define whether SIRT6 acts as a tumor suppressor by regulating metabolism-related gene expression in skin carcinogenesis. This work will also set up the basis to understand whether the Warburg effect plays a key role in skin cancer. Citation Format: Jee-Eun Choi, Carlos Sebastian, Raul Mostoslavsky. The role of glucose metabolism and SIRT6 in skin carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3366. doi:10.1158/1538-7445.AM2014-3366