Vitamin D induces SIRT1 activation through K610 deacetylation in colon cancer

Author:

García-Martínez José Manuel1,Chocarro-Calvo Ana1,Martínez-Useros Javier12,Fernández-Aceñero María Jesús3,Fiuza M Carmen4,Cáceres-Rentero José1,De la Vieja Antonio56,Barbáchano Antonio678,Muñoz Alberto678,Larriba María Jesús678,García-Jiménez Custodia1ORCID

Affiliation:

1. Area of Physiology, Faculty Health Sciences, University Rey Juan Carlos, Alcorcón

2. Translational Oncology Division, OncoHealth Institute, Health Research Institute-University Hospital Fundación Jiménez Díaz-Universidad Autónoma de Madrid

3. Department of Surgical Pathology, Hospital Clínico San Carlos

4. Department of Surgery, University Hospital Fundación Alcorcón-Universidad Rey Juan Carlos, Alcorcón

5. Unidad de Tumores Endocrinos (UFIEC), Instituto de Salud Carlos III, Majadahonda

6. CIBER de Cáncer, Instituto de Salud Carlos III

7. Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid

8. Instituto de Investigación Sanitaria del Hospital Universitario La Paz

Abstract

Posttranslational modifications of epigenetic modifiers provide a flexible and timely mechanism for rapid adaptations to the dynamic environment of cancer cells. SIRT1 is an NAD+-dependent epigenetic modifier whose activity is classically associated with healthy aging and longevity, but its function in cancer is not well understood. Here, we reveal that 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol), the active metabolite of vitamin D (VD), promotes SIRT1 activation through auto-deacetylation in human colon carcinoma cells, and identify lysine 610 as an essential driver of SIRT1 activity. Remarkably, our data show that the post-translational control of SIRT1 activity mediates the antiproliferative action of 1,25(OH)2D3. This effect is reproduced by the SIRT1 activator SRT1720, suggesting that SIRT1 activators may offer new therapeutic possibilities for colon cancer patients who are VD deficient or unresponsive. Moreover, this might be extrapolated to inflammation and other VD deficiency-associated and highly prevalent diseases in which SIRT1 plays a prominent role.

Funder

Agencia Estatal de Investigación

Instituto de Salud Carlos III

Comunidad de Madrid

Universidad Rey Juan Carlos

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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