Gamma-tocotrienol modifies methylation of HOXA10, IRF4 and RORα genes in CD4+ T-lymphocytes: Evidence from a syngeneic mouse model of breast cancer

Ammu K Radhakrishnan; Jeya Seela Anandha Rao; Shonia Subramaniam; Premdass Ramdas

doi:10.1016/j.crimmu.2021.10.001

Gamma-tocotrienol modifies methylation of HOXA10, IRF4 and RORα genes in CD4⁺ T-lymphocytes: Evidence from a syngeneic mouse model of breast cancer

Curr Res Immunol. 2021 Oct 9:2:169-174. doi: 10.1016/j.crimmu.2021.10.001. eCollection 2021.

Authors

Ammu K Radhakrishnan^{1

2}, Jeya Seela Anandha Rao^{1

3}, Shonia Subramaniam³, Premdass Ramdas⁴

Affiliations

¹ Pathology Division, School of Medicine, International Medical University, 57 000, Kuala Lumpur, Malaysia.
² Jeffery Cheah School of Medicine and Health Sciences, Monash University, 47500, Sunway, Selangor, Malaysia.
³ School of Postgraduate Studies, International Medical University, 57 000, Kuala Lumpur, Malaysia.
⁴ Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences, International Medical University, Kuala Lumpur, Malaysia.

Abstract

DNA methylation plays a crucial role in polarising naïve lymphocytes towards their various sub-populations to fight against many immune challenges including establishment of tumour. Gamma-tocotrienol (γT3) is a natural form of vitamin E, reported to possess anticancer and immunomodulatory effects. This study reports the anticancer effects of γT3 through modulation of DNA methylation in several genes in CD4⁺ T-lymphocytes using a syngeneic mouse model of breast cancer. Female BALB/c mice were fed with γT3 or vehicle (soy oil) for two-weeks via oral gavage before they were inoculated with 4T1 mouse mammary cancer cells. Supplementation continued until the mice were sacrificed. At autopsy, blood was collected via cardiac puncture and CD4⁺ T-cells were isolated for DNA extraction. The DNA was analysed using the EpiTech Methyl II mouse T-helper cell differentiation PCR array. γT3 supplementation reduced tumour growth in the tumour-induced animals and modulated host immune system by inducing changes in DNA methylation patterns of the HOXA10, IRF4 and RORα genes, which are involved in differentiation and clonal expansion of CD4⁺ T-cells. Results suggest that γT3 may enhance cell-mediated immune response in mice with breast cancer by inducing changes in DNA methylation pattern.

Keywords: Breast cancer; CD4+ T-lymphocytes; DNA methylation; Gamma-tocotrienol; HOXA10, Homeobox A10; IRF4, Interferon Regulatory Factor 4; RORα, Receptor-related orphan receptor-alpha; γT3, gamma-tocotrienol.