27-Hydroxycholesterol increases Myc protein stability via suppressing PP2A, SCP1 and FBW7 transcription in MCF-7 breast cancer cells

• Published in: Biochemical and biophysical research communications 2016-11, Vol.480 (3), p.328-333
• Main Authors: Ma, Li-Ming, Liang, Zi-Rui, Zhou, Ke-Ren, Zhou, Hui, Qu, Liang-Hu
• Format: Article
• Language: English
• Subjects: 27-Hydroxycholesterol; 60 APPLIED LIFE SCIENCES; Breast cancer; Cell Cycle Proteins - metabolism; DNA SEQUENCING; F-Box Proteins - metabolism; F-Box-WD Repeat-Containing Protein 7; FBW7; Gene Expression Regulation, Neoplastic; Humans; Hydroxycholesterols - metabolism; MAMMARY GLANDS; MCF-7 Cells; Myc protein stability; NEOPLASMS; Nuclear Proteins - metabolism; Phosphoprotein Phosphatases - metabolism; PP2A; Protein Phosphatase 2 - metabolism; Proto-Oncogene Proteins c-myc - metabolism; SCP1; STABILITY; TRANSCRIPTION FACTORS; Transcriptional Activation; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.10.038

27-hydroxycholesterol (27-HC), the most abundant metabolite of cholesterol, is a risk factor for breast cancer. It can increase the proliferation of breast cancer cells and promote the metastasis of breast tumours in mouse models. Myc is a critical oncoprotein overexpressed in breast cancer. However, whether 27-HC affects Myc expression has not been reported. In the current study, we aimed to investigate the effects of 27-HC on Myc and the underlying mechanisms in MCF-7 breast cancer cells. Our data demonstrated that 27-HC activated Myc via increasing its protein stability. Three key negative modulators of Myc protein stability, PP2A, SCP1 and FBW7, were suppressed by 27-HC at the transcriptional level. We performed a data-mining analysis of the chromatin immunoprecipitation with next-generation DNA sequencing (ChIP-Seq) data in the ChIPBase, and discovered that a number of putative transcription factors (TFs), including Myc itself, were involved in the transcriptional regulation of PP2A, SCP1 and FBW7. Our results provide a novel mechanistic insight into the activation of Myc by 27-HC via transcriptional repression of PP2A, SCP1 and FBW7 to increase Myc protein stability in breast cancer cells. [Display omitted] •27-Hydroxycholesterol (27-HC) activates Myc via increasing its protein stability.•27-HC inhibits PP2A and SCP1 transcription to block pS62-Myc dephosphorylation.•27-HC suppresses FBW7 transcription to prevent pT58-Myc degradation.