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Histone Post-Translational Modifications and the Development of Merkel Cell Carcinoma

By: Joshua D. Madera, MS
Posted: Friday, May 13, 2022

The onset and development of Merkel cell carcinoma may be regulated by histone post-translational modifications, according to a study published in Frontiers in Oncology. However, further analyses regarding the dysregulation of post-translational modifications and their relationship with Merkel cell carcinoma are necessary, explained John Charles Rotondo, PhD, of the University of Ferrara, Italy, and colleagues.

The dysregulation of histone acetylation leads to host immune-surveillance escape in patients with Merkel cell carcinoma. According to the study authors, this may be due to the downregulation of major compatibility complex I (MHC) on tumor cell surfaces, leading to decreased recognition by T cells. In addition, impairment in acetylation leads to dysregulation of the proto-oncogene c-Myc. Increased c-Myc expression has been associated with the pathogenesis of Merkel cell carcinoma through the interaction of acetylated lysine 27 enrichment at histone H3 and bromodomain protein 4.

Furthermore, the relationship between histone methylation and increased expression of the lysine-specific demethylase 1 (LSD1) enzyme has received attention in an attempt to develop novel therapies for Merkel cell carcinoma. In vitro studies have demonstrated that inhibition of LSD1 induces cell apoptosis and tumor growth inhibition, making this enzyme a prime target for therapeutic intervention. Moreover, the specific methyltransferase involved in the development of Merkel cell carcinoma has been identified as PRDM8.

The role of histone phosphorylation may also play a role in Merkel cell carcinoma, the study authors proposed, such that H3 threonine 80 phosphorylation and H3 phosphorylation may serve as prognostic markers. Specifically, they may indicate the presence of mitotic figures and G2-positive tumor nuclei. In addition, phosphorylation of histones involved in the DNA damage response pathway activation and ataxia telangiectasia–mutant activation have also been linked to Merkel cell carcinoma.

Disclosures: For full disclosures of the study authors, visit frontiersin.org.


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