|Title||Prostaglandin E down-regulates sirtuin 1 (SIRT1), leading to elevated levels of aromatase, providing insights into the obesity-breast cancer connection.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Subbaramaiah K, Iyengar NM, Morrow M, Elemento O, Zhou XKathy, Dannenberg AJ|
|Journal||J Biol Chem|
|Date Published||2019 01 04|
|Keywords||Aromatase, Breast Neoplasms, Cell Line, Transformed, Dinoprostone, Female, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Neoplasm Proteins, Obesity, p300-CBP Transcription Factors, Response Elements, Resveratrol, Sirtuin 1|
Obesity increases the risk of hormone receptor-positive breast cancer in postmenopausal women. Levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis, are increased in the breast tissue of obese women. Both prostaglandin E (PGE) and hypoxia-inducible factor 1α (HIF-1α) contribute to the induction of aromatase in adipose stromal cells (ASCs). Sirtuin 1 (SIRT1) binds, deacetylates, and thereby inactivates HIF-1α. Here, we sought to determine whether SIRT1 also plays a role in regulating aromatase expression. We demonstrate that reduced SIRT1 levels are associated with elevated levels of acetyl-HIF-1α, HIF-1α, and aromatase in breast tissue of obese compared with lean women. To determine whether these changes were functionally linked, ASCs were utilized. In ASCs, treatment with PGE, which is increased in obese individuals, down-regulated SIRT1 levels, leading to elevated acetyl-HIF-1α and HIF-1α levels and enhanced aromatase gene transcription. Chemical SIRT1 activators (SIRT1720 and resveratrol) suppressed the PGE-mediated induction of acetyl-HIF-1α, HIF-1α, and aromatase. Silencing of p300/CBP-associated factor (PCAF), which acetylates HIF-1α, blocked PGE-mediated increases in acetyl-HIF-1α, HIF-1α, and aromatase. SIRT1 overexpression or PCAF silencing inhibited the interaction between HIF-1α and p300, a coactivator of aromatase expression, and suppressed p300 binding to the aromatase promoter. PGE acted via prostaglandin E2 receptor 2 (EP) and EP to induce activating transcription factor 3 (ATF3), a repressive transcription factor, which bound to a CREB site within the promoter and reduced SIRT1 levels. These findings suggest that reduced SIRT1-mediated deacetylation of HIF-1α contributes to the elevated levels of aromatase in breast tissues of obese women.
|Alternate Journal||J. Biol. Chem.|
|PubMed Central ID||PMC6322870|
|Grant List||P30 CA008748 / CA / NCI NIH HHS / United States |
R01 CA215797 / CA / NCI NIH HHS / United States
U54 CA210184 / CA / NCI NIH HHS / United States
Prostaglandin E down-regulates sirtuin 1 (SIRT1), leading to elevated levels of aromatase, providing insights into the obesity-breast cancer connection.
Submitted by chz4003 on August 12, 2019 - 12:44pm