Epigenetic Silencing Mediated through Activated PI3K/AKT Signaling in Breast Cancer

Abstract

Trimethylation of histone 3 lysine 27 (H3K27me3) is a critical epigenetic mark for the maintenance of gene silencing. Additional accumulation of DNA methylation in target loci is thought to cooperatively support this epigenetic silencing during tumorigenesis. However, molecular mechanisms underlying the complex interplay between the two marks remain to be explored. Here we show that activation of PI3K/AKT signaling can be a trigger of this epigenetic processing at many downstream target genes. We also find that DNA methylation can be acquired at the same loci in cancer cells, thereby reinforcing permanent repression in those losing the H3K27me3 mark. Because of a link between PI3K/AKT signaling and epigenetic alterations, we conducted epigenetic therapies in conjunction with the signaling-targeted treatment. These combined treatments synergistically relieve gene silencing and suppress cancer cell growth in vitro and in xenografts. The new finding has important implications for improving targeted cancer therapies in the future. Cancer Res; 71(5);

Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8+ T-cell killing

“…The molecular link between CD28 activation and proteasome subunit downregulation remains to be determined, but it is likely to involve the PI3K/AKT pathway for several reasons: (1) binding of CD28 on MM cells triggers PI3K/AKT signaling 15 ; (2) PI3K/AKT signaling induces epigenetic silencing in tumors 32,33 ; and (3) treatment of tumor plasma cells with decitabine, a potent DNA methyltransferase inhibitor, restores proteasome subunit expression, as we have already reported. 13 Additional studies are also required to understand whether the reduced killing, by CD8…”

Histone Modifications Are Associated with Δ9-Tetrahydrocannabinol-mediated Alterations in Antigen-specific T Cell Responses

“…However, THC could indirectly regulate the activity of enzymes involved in histone methylation. For example, cannabinoids have been shown to down-regulate the PI3K/ AKT signaling pathway (66,67), a pathway also known to cause global alterations of H3K27me3 (68). On the other hand, some studies showed that administration of THC increases phosphorylation of AKT in the mouse brain through CB1 (69).…”

A Phase Ib Study of the Effects of Black Raspberries on Rectal Polyps in Patients with Familial Adenomatous Polyposis

“…As will be noted below, adenomas from a total of 2 subjects treated with orally administered BRBs plus BRB suppositories and 1 subject treated with BRB suppositories only did not respond to berry treatment. These subjects had more rectal adenomas at the end of the trial than at baseline, and the adenomas were used for the MBDCap-seq assay to determine whether differences in the response of adenomas from nonresponders and responders might be due to differences in effects of the BRBs on genome-wide DNA methylation (23). Unfortunately, due to other uses, adjacent normal tissues from two of the nonresponders were not available for the MBDCap-seq assay.…”