The tumor suppressor role and epigenetic regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in cancer and tumor microenvironment (TME).

Abstract

Oxidative stress and inflammation may initiate carcinogenesis and facilitate metastasis via activation of pro-inflammatory signaling network. The side product of arachidonic acid processing by cyclooxygenase-2 (COX-2), the prostaglandin E2 (PGE2), plays a key role in various metabolic disorders and during inflammation-mediated tumorigenesis. It has been demonstrated that PGE2 increases the proliferation, migration, invasion, metastasis, and resistance of cancer cells to apoptosis and other forms of programmed cell death. The expression level of PGE2 metabolizing enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is often decreased in various malignancies. However, the role of 15-PGDH and PGE2 in the regulation of carcinogenesis remains controversial. Numerous cancer cell lines and mouse models have demonstrated the role of 15-PGDH as a tumor suppressor. Downregulation of 15-PGDH increased cancer cell proliferation, migration, anchorage independent growth, colony formation while overexpression reversed these effects, by inducing apoptosis and cell cycle arrest in vitro and in vivo. The expression of 15-PGDH is regulated by various mechanisms, including (a) epigenetic alterations (methylation of promoter region, histone deacetylases, microRNAs (miR-21) (miR-26a/b, miR-106b-5p, miR-146b-3p, miR-155, miR-218-5p, and miR-620)); and (b) dysregulated oxidative stress and associated mediators (elevated levels of growth factors and proinflammatory cytokines (such as IL1β and TNFα)). Several transcription factors, such as HNF3β, β-catenin, Snail, Slug, can bind to 15-PGDH promoter region and downregulate the enzyme expression. In contrast, the expression of 15-PGDH can be upregulated by several anti-inflammatory cytokines and anti-cancer agents, such as IL10 and vitamin D. The functional activity of 15-PGDH protein can be modulated by signaling effectors and oxidative stress, including increased production of reactive oxygen species (ROS). However, the role of oxidative stress regulator protein, i.e., nuclear factor erythroid 2-related factor 2 (Nrf2), in the control of 15-PGDH expression remains unclear. This article provides insights and comprehensive overview of the tumor suppressor role of 15-PGDH in various cancers. Epigenetic and post-translational mechanisms regulating 15-PGDH expression and the role of novel ROS-Nrf2-15-PGDH axis upstream of 15-PGDH expression were discussed and accented as potential drug targets.