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

Hases, Linnea; Archer, Amena; Indukuri, Rajitha; Birgersson, Madeleine; Savva, Christina; Korach-André, Marion; Williams, Cecilia

doi:10.1038/s41598-020-73166-1

Cited by 36 publications

(50 citation statements)

References 70 publications

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“…In addition, the administration of exogenous estrogens (hormone replacement therapy) shows a protective effect against CRC [ 135 ]. A transcriptomic study has suggested that estrogen regulates the colon environment in a state of high-fat diet-induced obesity in a sex-specific manner [ 136 ]. A high-fat diet disrupts clock genes and increases macrophage infiltration in both male and female mice, while it also promotes epithelial cell proliferation in male mice.…”

Section: Sex Differences In the Incidence Of Major Gastrointestinamentioning

confidence: 99%

“…A high-fat diet disrupts clock genes and increases macrophage infiltration in both male and female mice, while it also promotes epithelial cell proliferation in male mice. ER-β activation reverses these alterations, indicating that estrogen might play a protective role against the risk of obesity-associated CRC [ 136 ].…”

Section: Sex Differences In the Incidence Of Major Gastrointestinamentioning

confidence: 99%

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Sex Differences in the Incidence of Obesity-Related Gastrointestinal Cancer

Heo

Kim

Sung

2021

IJMS

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Cancer is the second leading cause of death worldwide, with 9.6 million people estimated to have died of cancer in 2018. Excess body fat deposition is a risk factor for many types of cancer. Men and women exhibit differences in body fat distribution and energy homeostasis regulation. This systematic review aimed to understand why sex disparities in obesity are associated with sex differences in the incidence of gastrointestinal cancers. Cancers of the esophagus, liver, and colon are representative gastrointestinal cancers, and obesity is a convincing risk factor for their development. Numerous epidemiological studies have found sex differences in the incidence of esophageal, liver, and colorectal cancers. We suggest that these sexual disparities are partly explained by the availability of estrogens and other genetic factors regulating inflammation, cell growth, and apoptosis. Sex differences in gut microbiota composition may contribute to differences in the incidence and phenotype of colorectal cancer. To establish successful practices in personalized nutrition and medicine, one should be aware of the sex differences in the pathophysiology and associated mechanisms of cancer development.

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Section: Sex Differences In the Incidence Of Major Gastrointestinamentioning

confidence: 99%

Section: Sex Differences In the Incidence Of Major Gastrointestinamentioning

confidence: 99%

Sex Differences in the Incidence of Obesity-Related Gastrointestinal Cancer

Heo

Kim

Sung

2021

IJMS

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“…There are also molecular sex differences where women have a higher number of B-Raf proto-oncogene, serine/threonine kinase ( BRAF ) mutations and a higher microsatellite instability (MSI) status compared to men, whereas men have a higher number of NRAS proto-oncogene, GTPase ( NRAS ) mutations [ 12 ]. Recently, we identified that mice exhibit sex differences in their colon transcriptomes [ 13 ]. Some of these differences may be related to estrogen signaling [ 8 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

The Importance of Sex in the Discovery of Colorectal Cancer Prognostic Biomarkers

Hases

Ibrahim

Chen

et al. 2021

IJMS

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Colorectal cancer (CRC) is the third leading cause of cancer deaths. Advances within bioinformatics, such as machine learning, can improve biomarker discovery and ultimately improve CRC survival rates. There are clear sex differences in CRC characteristics, but the impact of sex has not been considered with regards to CRC biomarkers. Our aim here was to investigate sex differences in the transcriptome of a normal colon and CRC, and between paired normal and tumor tissue. Next, we attempted to identify CRC diagnostic and prognostic biomarkers and investigate if they are sex-specific. We collected paired normal and tumor tissue, performed RNA-seq, and applied feature selection in combination with machine learning to identify the top CRC diagnostic biomarkers. We used The Cancer Genome Atlas (TCGA) data to identify sex-specific CRC diagnostic biomarkers and performed an overall survival analysis to identify sex-specific prognostic biomarkers. We found transcriptomic sex differences in both the normal colon tissue and in CRC. Forty-four of the top-ranked biomarkers were sex-specific and 20 biomarkers showed a sex-specific prognostic value. Our data show the importance of sex in the discovery of CRC biomarkers. We propose 20 sex-specific CRC prognostic biomarkers, including ESM1, GUCA2A, and VWA2 for males and CLDN1 and FUT1 for females.

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“…In our recent studies, we have showed that ERβ can modulate the impact of TNFα-NFκB activity in CRC cell lines and in vivo using the AOM-DSS mouse model ( 22 ). We have also demonstrated that intestinal ERβ regulates the expression of the circadian clock gene Bmal1 ( Arntl1 ) in colon of HFD-fed mice ( 56 ). Here, in addition to identifying p65-binding sites, we demonstrate that the activation of the TNFα-NFκB axis impacts the expression of circadian genes.…”

Section: Discussionmentioning

confidence: 94%

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

Cited by 36 publications

References 70 publications

Sex Differences in the Incidence of Obesity-Related Gastrointestinal Cancer

Sex Differences in the Incidence of Obesity-Related Gastrointestinal Cancer

The Importance of Sex in the Discovery of Colorectal Cancer Prognostic Biomarkers

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

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