Prostaglandin E(2) down-regulates sirtuin 1 (SIRT1), leading to elevated levels of aromatase, providing insights into the obesity-breast cancer connection Journal Article


Authors: Subbaramaiah, K.; Iyengar, N. M.; Morrow, M.; Elemento, O.; Zhou, X. K.; Dannenberg, A. J.
Article Title: Prostaglandin E(2) down-regulates sirtuin 1 (SIRT1), leading to elevated levels of aromatase, providing insights into the obesity-breast cancer connection
Abstract: 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 E2 (PGE2) and hypoxia-inducible factor 1 (HIF-1) contribute to the induction of aromatase in adipose stromal cells (ASCs). Sirtuin 1 (SIRT1) binds, deacetylates, and thereby inactivates HIF-1. 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-1, HIF-1, 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 PGE2, which is increased in obese individuals, down-regulated SIRT1 levels, leading to elevated acetyl–HIF-1 and HIF-1 levels and enhanced aromatase gene transcription. Chemical SIRT1 activators (SIRT1720 and resveratrol) suppressed the PGE2-mediated induction of acetyl–HIF-1, HIF-1, and aromatase. Silencing of p300/CBP-associated factor (PCAF), which acetylates HIF-1, blocked PGE2-mediated increases in acetyl–HIF-1, HIF-1, and aromatase. SIRT1 overexpression or PCAF silencing inhibited the interaction between HIF-1 and p300, a coactivator of aromatase expression, and suppressed p300 binding to the aromatase promoter. PGE2 acted via prostaglandin E2 receptor 2 (EP2) and EP4 to induce activating transcription factor 3 (ATF3), a repressive transcription factor, which bound to a CREB site within the SIRT1 promoter and reduced SIRT1 levels. These findings suggest that reduced SIRT1-mediated deacetylation of HIF-1 contributes to the elevated levels of aromatase in breast tissues of obese women. © 2019 Subbaramaiah et al.
Journal Title: Journal of Biological Chemistry
Volume: 294
Issue: 1
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2019-01-04
Start Page: 361
End Page: 371
Language: English
DOI: 10.1074/jbc.RA118.005866
PUBMED: 30409902
PROVIDER: scopus
PMCID: PMC6322870
DOI/URL:
Notes: Article -- Export Date: 1 February 2019 -- Source: Scopus
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MSK Authors
  1. Monica Morrow
    448 Morrow
  2. Neil Mukund Iyengar
    63 Iyengar