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Epigenetic marks, such as histone modifications, have been implicated in the regulation of the aging process by controlling gene expression in response to environmental stimuli (i.e. diet) and stress signals occurring throughout life. Consequently, undesirable epigenetic alterations have been linked to shortened lifespan and development of age-associated diseases such as cancer. However, the potential reversibility of these epigenetic alterations offers exciting opportunities to delay aging and prevent the manifestation of diseases like cancer. Our group has recently revealed a role for histone N-alpha-terminal acetylation in cellular longevity and carcinogenesis, and ongoing work is aiming to understand the precise molecular mechanisms employed by this histone modification and its associated enzyme NAA40 during aging and cancer. Through these research activities we anticipate to inform strategies for molecular diagnostics as well as new interventions for promoting healthy lifespan and for therapy of age-associated diseases.

Histone N-alpha-terminal acetylation in aging and cancer: Project

NAA40 is commonly upregulated in cancers leading to high levels of N-alpha-terminal acetylation on histone H4. As a result, the antagonistic phosphorylation on histone H4 serine 1 is reduced leading to the activation of Slug gene inducing lung cancer cell migration and metastasis. Alternatively, in colorectal cancer cells NAA40-mediated histone H4 N-alpha-terminal acetylation promotes the expression of PRMT5 which subsequently activates the expression of oncogenes stimulating cancer cell growth. (Demetriadou C et al., 2019; Demetriadou C et al., 2020)

Histone N-alpha-terminal acetylation in aging and cancer: Image

NAA40 and its associated histone N-terminal acetylation control cellular lifespan in yeast. Calorie restriction (CR) reduces the levels of NAA40 and H4 N-terminal acetylation. Lower levels of H4 N-terminal acetylation result in increased methylation at H4R3. Under these conditions several stress response genes, including the CR-responsive nicotinamidase PNC1, are induced leading to extension in cellular longevity. (Molina-Serrano D et al., 2016; Molina-Serrano D et al., 2019)

Histone N-alpha-terminal acetylation in aging and cancer: Image
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