Goeman F.,Italian National Cancer Institute |
De Nicola F.,Italian National Cancer Institute |
De Meo P.D.,HPC CINECA |
Pallocca M.,Italian National Cancer Institute |
And 7 more authors.
Journal of Steroid Biochemistry and Molecular Biology | Year: 2014
There is growing evidence that 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) plays a role in breast cancer prevention and survival. It elicits a variety of antitumor activities like controlling cellular differentiation, proliferation and angiogenesis. Most of its biological effects are exerted via its nuclear receptor which acts as a transcriptional regulator. Here, we carried out a genome-wide investigation of the primary transcriptional targets of 1α,25(OH)2D3 in breast epithelial cancer cells using RNA-Seq technology. We identified early transcriptional targets of 1α,25(OH)2D3 involved in adhesion, growth regulation, angiogenesis, actin cytoskeleton regulation, hexose transport, inflammation and immunomodulation, apoptosis, endocytosis and signaling. Furthermore, we found several transcription factors to be regulated by 1α,25(OH)2D3 that subsequently amplify and diversify the transcriptional output driven by 1α,25(OH)2D3 leading finally to a growth arrest of the cells. Moreover, we could show that 1α,25(OH)2D3 elevates the trimethylation of histone H3 lysine 4 at several target gene promoters. Our present transcriptomic analysis of differential expression after 1α,25(OH)2D3 treatment provides a resource of primary 1α,25(OH)2D3 targets that might drive the antiproliferative action in breast cancer epithelial cells. © 2014 Elsevier Ltd. All rights reserved. Source
Desantis A.,Italian National Cancer Institute |
Bruno T.,Italian National Cancer Institute |
Catena V.,Italian National Cancer Institute |
Catena V.,University of LAquila |
And 21 more authors.
EMBO Journal | Year: 2015
Mammalian target of rapamycin (mTOR) is a key protein kinase that regulates cell growth, metabolism, and autophagy to maintain cellular homeostasis. Its activity is inhibited by adverse conditions, including nutrient limitation, hypoxia, and DNA damage. In this study, we demonstrate that Che-1, a RNA polymerase II-binding protein activated by the DNA damage response, inhibits mTOR activity in response to stress conditions. We found that, under stress, Che-1 induces the expression of two important mTOR inhibitors, Redd1 and Deptor, and that this activity is required for sustaining stress-induced autophagy. Strikingly, Che-1 expression correlates with the progression of multiple myeloma and is required for cell growth and survival, a malignancy characterized by high autophagy response. Synopsis The RNA polymerase-binding protein Che-1 inhibits the mTOR pathway in response to stress, thereby sustaining autophagy and multiple myeloma cell growth. Che-1 inhibits mTOR activity in response to cellular stress. Che-1 sustains Redd1 and Deptor expressions. Che-1 regulates autophagy by inhibiting mTORC1 activity. Che-1 expression increases during multiple myeloma progression and is required for cell survival. The RNA polymerase-binding protein Che-1 inhibits the mTOR pathway in response to stress, thereby sustaining autophagy and multiple myeloma cell growth. © 2015 Regina Elena Cancer Institute. Source