SIRT1 regulates Mxd1 during malignant melanoma progression

Abstract

In a murine melanoma model, malignant transformation promoted by a sustained stress condition was causally related to increased levels of reactive oxygen species resulting in DNA damage and massive epigenetic alterations. Since the chromatin modifier Sirtuin-1 (SIRT1) is a protein attracted to double-stranded DNA break (DSB) sites and can recruit other components of the epigenetic machinery, we aimed to define the role of SIRT1 in melanomagenesis through our melanoma model. The DNA damage marker, γH2AX was found increased in melanocytes after 24 hours of deadhesion, accompanied by increased SIRT1 expression and decreased levels of its target, H4K16ac. Moreover, SIRT1 started to be associated to DNMT3B during the stress condition, and this complex was maintained along malignant progression. Mxd1 was identified by ChIP-seq among the DNA sequences differentially associated with SIRT1 during deadhesion and was shown to be a common target of both, SIRT1 and DNMT3B. In addition, Mxd1 was found downregulated from pre-malignant melanocytes to metastatic melanoma cells. Treatment with DNMT inhibitor 5AzaCdR reversed the Mxd1 expression. Sirt1 stable silencing increased Mxd1 mRNA expression and led to down-regulation of MYC targets, such as Cdkn1a, Bcl2 and Psen2, whose upregulation is associated with human melanoma aggressiveness and poor prognosis. We demonstrated a novel role of the stress responsive protein SIRT1 in malignant transformation of melanocytes associated with deadhesion. Mxd1 was identified as a new SIRT1 target gene. SIRT1 promoted Mxd1 silencing, which led to increased activity of MYC oncogene contributing to melanoma progression.

Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

“…Alteration of methylation status with aging changes chromatin accessibility, resulting in aberrant gene transcription, as well as genomic instability. These factors may be key regulators of the aging process and contributors to the development of aging-associated diseases [ 208 , 209 , 210 , 211 , 212 , 213 , 214 ], including neoplastic growth [ 189 , 215 , 216 , 217 , 218 , 219 ] and aging itself [ 220 , 221 , 222 , 223 ]. For example, when methylation arises in the CpG islands encoding genes that suppress aging-associated disease(s) and/or when demethylation arises in the CpG islands encoding genes that cause aging-associated disease(s), the onset and the progression of aging-associated disease(s) are accelerated.…”

The Role of SIRT1 on DNA Damage Response and Epigenetic Alterations in Cancer

“…The role of SIRT1 in cancer seems contradictory. SIRT1 overexpression has been described in many cancers compared to normal tissues, including leukemia [53], non-melanoma [51] and melanoma skin cancer [54,55], prostate [56], and colon carcinomas [57]. On the other hand, SIRT1 down regulation has also been observed in other neoplasms, such as breast cancer and hepatic cell carcinomas [52].…”

Gene co-expression and histone modification signatures are associated with melanoma progression, epithelial-to-mesenchymal transition, and metastasis

“…Among these hub genes, GAB2 is an adaptor protein commonly overexpressed in melanoma that upregulates RAS-ERK and PI3K-AKT pathways and promotes melanoma metastasis [ 34 ]. Psen2 encodes the protein presenilin-2, a MYC target increased in melanoma cells [ 35 ], whereas Mapkapk3 is a member of the p38 pathway that promotes autophagy [ 36 ]. TTYH2, in turn, is a volume-regulated anion channel that regulates transcription factors involved in EMT and is critical for the migration of osteosarcoma cells [ 37 ].…”