Intestinal estrogen receptor beta suppresses colon inflammation and tumorigenesis in both sexes

Hases, Linnea; Indukuri, Rajitha; Birgersson, Madeleine; Nguyen-Vu, Trang; Lozano, Rodrigo; Saxena, Ashish; Hartman, Johan; Frasor, Jonna; Gustafsson, Jan‐Åke; Katajisto, Pekka; Archer, Amena; Williams, Cecilia

doi:10.1016/j.canlet.2020.06.021

Cited by 46 publications

(55 citation statements)

References 33 publications

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“…Although the etiology of obesity and IBD is different, both are characterized by gut inflammation with common inflammatory pathways including TNFα, IL6, and IL1b [54][55][56][57] . We have recently shown in a colitis-induced CRC mouse model that ERβ in intestinal epithelial cells can downregulate the TNFα/NFkB signaling 37 . Together, our data suggest that specific activation of intestinal ERβ may have a beneficial impact to modulate gut inflammation in both pathologies.…”

Section: Discussionmentioning

confidence: 99%

“…4C). In addition, we have previously shown that ERβ can cross-talk with and regulate NFκB signaling in both human colon cell lines and mouse in vivo colon (ERβ-intestinal knockout mice) 37 . In line with this, we here observed that HFD-induced expression of several NFκB target genes (Cxcl5, Nos2) in females, which were blocked by both ERβ (DPN) and ERα (PPT).…”

Section: Erβ-selective Agonist Impacts Fat Distribution and Reduces Cmentioning

confidence: 99%

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High-fat diet and estrogen impacts the colon and its transcriptome in a sex-dependent manner

Hases

Archer

Indukuri

et al. 2020

Sci Rep

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There is a strong association between obesity and colorectal cancer (CRC), especially in men, whereas estrogen protects against both the metabolic syndrome and CRC. Colon is the first organ to respond to high-fat diet (HFD), and estrogen receptor beta (ERβ) can attenuate CRC development. How estrogen impacts the colon under HFD and related sex differences has, however, not been investigated. To dissect this, mice were fed control diet or HFD for 13 weeks and administered receptor-selective estrogenic ligands for the last three weeks. We recorded impact on metabolism, colon crypt proliferation, macrophage infiltration, and the colon transcriptome. We found clear sex differences in the colon transcriptome and in the impact by HFD and estrogens, including on clock genes. ERα-selective activation reduced body weight and generated systemic effects, whereas ERβ-selective activation had local effects in the colon, attenuating HFD-induced macrophage infiltration and epithelial cell proliferation. We here demonstrate how HFD and estrogens modulate the colon microenvironment in a sex- and ER-specific manner.

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Section: Discussionmentioning

confidence: 99%

Section: Erβ-selective Agonist Impacts Fat Distribution and Reduces Cmentioning

confidence: 99%

High-fat diet and estrogen impacts the colon and its transcriptome in a sex-dependent manner

Hases

Archer

Indukuri

et al. 2020

Sci Rep

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“…The experimental overexpression of ERb in colon cancer cells revealed that ERb inhibits proliferation by blocking of the cell cycle in G1-S phase (78) possibly involving repression of mir-17 (79), and stimulating apoptosis (80). Moreover, in addition to anti-tumorigenic actions, ERb induces anti-inflammatory signaling in CRC cells (81). Other protective mechanisms attributed to ERb in the colon include upregulation of tight junction proteins occludin (OCLN) and JAMA (F11R) to preserve homeostasis of paracellular permeability (82).…”

Section: Estrogen Receptorsmentioning

confidence: 99%

Sexual Dimorphism in Colon Cancer

et al. 2020

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A higher incidence of colorectal cancer (CRC) is found in males compared to females. Young women (18–44 years) with CRC have a better survival outcome compared to men of the same age or compared to older women (over 50 years), indicating a global incidence of sexual dimorphism in CRC rates and survival. This suggests a protective role for the sex steroid hormone estrogen in CRC development. Key proliferative pathways in CRC tumorigenesis exhibit sexual dimorphism, which confer better survival in females through estrogen regulated genes and cell signaling. Estrogen regulates the activity of a class of Kv channels (KCNQ1:KCNE3), which control fundamental ion transport functions of the colon and epithelial mesenchymal transition through bi-directional interactions with the Wnt/β-catenin signalling pathway. Estrogen also modulates CRC proliferative responses in hypoxia via the novel membrane estrogen receptor GPER and HIF1A and VEGF signaling. Here we critically review recent clinical and molecular insights into sexual dimorphism of CRC biology modulated by the tumor microenvironment, estrogen, Wnt/β-catenin signalling, ion channels, and X-linked genes.

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“…The hormone estrogen has been shown to reduce CRC incidence (16)(17)(18)(19)(20). Estrogen mainly acts through three receptors, of which estrogen receptor beta (ERb, ESR2) is present in epithelial colon and rectal cells (21,22). We have recently shown that intestinal epithelial ERb in vivo protects from the epithelial damage caused by TNFa and prevents tumor formation (22).…”

Section: Introductionmentioning

confidence: 99%

“…Estrogen mainly acts through three receptors, of which estrogen receptor beta (ERb, ESR2) is present in epithelial colon and rectal cells (21,22). We have recently shown that intestinal epithelial ERb in vivo protects from the epithelial damage caused by TNFa and prevents tumor formation (22). Also, when reintroduced into CRC cell lines, ERb has antiproliferative and tumor-suppressive activity (22,23).…”

Section: Introductionmentioning

confidence: 99%

Estrogen Receptor Beta Influences the Inflammatory p65 Cistrome in Colon Cancer Cells

Indukuri

Hases²,

Archer³

et al. 2021

Front. Endocrinol.

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Inflammation is a primary component of both initiation and promotion of colorectal cancer (CRC). Cytokines secreted by macrophages, including tumor necrosis factor alpha (TNFα), activates the pro-survival transcription factor complex NFκB. The precise mechanism of NFκB in CRC is not well studied, but we recently reported the genome-wide transcriptional impact of TNFα in two CRC cell lines. Further, estrogen signaling influences inflammation in a complex manner and suppresses CRC development. CRC protective effects of estrogen have been shown to be mediated by estrogen receptor beta (ERβ, ESR2), which also impacts inflammatory signaling of the colon. However, whether ERβ impacts the chromatin interaction (cistrome) of the main NFκB subunit p65 (RELA) is not known. We used p65 chromatin immunoprecipitation followed by sequencing (ChIP-Seq) in two different CRC cell lines, HT29 and SW480, with and without expression of ERβ. We here present the p65 colon cistrome of these two CRC cell lines. We identify that RELA and AP1 motifs are predominant in both cell lines, and additionally describe both common and cell line-specific p65 binding sites and correlate these to transcriptional changes related to inflammation, migration, apoptosis and circadian rhythm. Further, we determine that ERβ opposes a major fraction of p65 chromatin binding in HT29 cells, but enhances p65 binding in SW480 cells, thereby impacting the p65 cistrome differently in the two cell lines. However, the biological functions of the regulated genes appear to have similar roles in both cell lines. To our knowledge, this is the first time the p65 CRC cistrome is compared between different cell lines and the first time an influence by ERβ on the p65 cistrome is investigated. Our work provides a mechanistic foundation for a better understanding of how estrogen influences inflammatory signaling through NFκB in CRC cells.

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Intestinal estrogen receptor beta suppresses colon inflammation and tumorigenesis in both sexes

Cited by 46 publications

References 33 publications

High-fat diet and estrogen impacts the colon and its transcriptome in a sex-dependent manner

High-fat diet and estrogen impacts the colon and its transcriptome in a sex-dependent manner

Sexual Dimorphism in Colon Cancer

Estrogen Receptor Beta Influences the Inflammatory p65 Cistrome in Colon Cancer Cells

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