Histone methyltransferase EHMT2 degradation by propionate derived from Bacteroides thetaiotaomicron induced colon cancer apoptosis via epigenetic regulation of TNFAIP1

Abstract

BackgroundBacteroides thetaiotaomicron (BT) is the second most commonly isolated bacterium in the human microbiome after B. fragilis and is involved in the hydrolysis of glycosidic bonds in dietary carbohydrates. Although the human microbiome has recently been shown to affect colorectal cancer (CRC) treatment, the mode of action (MOA) between the microbiome and CRC is still unclear. MethodsTo assess the colon cancer apoptosis, we performed western blot, qRT-PCR and FACS analysis using BT supernatant (Sup), sodium propionate (SP), and EHMT2 specific siRNA. Using RNA-seq analysis and ChIP-seq analysis, we identified HECTD2 (E3 ligase) and TNFAIP1 (EHMT2 target) genes. The antitumor activity of EHMT2 was determined by an in vivo xenograft model. ResultsWe selected propionate derived from BT and showed that it suppressed CRC growth by promoting proteasomal degradation of EHMT2 through HECTD2 upregulation. Moreover, downregulation of EHMT2 reduced the level of H3K9me2 on the promoter region of TNFAIP1, and subsequently, upregulation of TNFAIP1 induced apoptosis of CRC cells. Finally, we performed an in vivo study using BIX01294 to inactivate EHMT2 and observed a reduction in the tumor size of the CRC xenograft models. ConclusionsWe suggest anticancer effects of BT and EHMT2 as therapeutic targets for colon cancer treatment, and we will provide the possibility for synergistic effects of an EHMT2 inhibitor and BT in CRC treatment. *Authors share co-first authorshipBackground Colorectal cancer (CRC) is a major cancer worldwide. Although chemotherapy (5-fluorouracil (5-FU) and oxaliplatin) and targeted therapy (cetuximab and bevacizumab) are used to treat this disease, new therapeutic methods are needed to reduce the side effects and increase the success rate of CRC 4 treatment [1][2][3]. Recently, the human microbiome, including metabolites and microbiota, has been studied to identify alternative new CRC treatments [4][5][6].In the human body, the microbiota mainly colonizes the large intestine and promotes food digestion, regulation of the human immune system, production of vitamins (B12, K, riboflavin), and protection against disease-related bacteria [7][8][9]. In the colon, the Bacteroides genus is a major group of the human microbiome, and Bacteroides thetaiotaomicron (BT) is the second most commonly isolated bacteria after B. fragilis [10][11][12]. BT is a gram-negative obligate anaerobe. This bacterium is involved in polysaccharide metabolism, such as hydrolysis of glycosidic bonds in dietary carbohydrates [10]. In colon cancer, the major bacterium B. fragilis showed suppression of inflammation-associated CRC development via polysaccharide A production [13]. In other words, B. fragilis-derived toxins induced CRC development [14]. Although BT is the second most commonly isolated bacterium in the human microbiome, the relationship between BT and CRC is still unclear. Thus, we examined the anticancer effects of BT using CRC cell lines and elucidated the molecular mechanism of BT-induced apoptosis of CRC cells via epig...

Gut microbiota in the combined treatment of colorectal cancer using autoprobiotics

“…Несколько гистонметилтрансфераз и деметилаз сверхэкспрессируются и участвуют в росте КРР и метастазировании посредством эпигенетической регуляции. Деградация гистонметилтрансферазы EHMT2 пропионатом, продуцируемым B. thetaiotaomicron, индуцирует апоптоз раковых клеток толстой кишки посредством эпигенетической регуляции TNFAIP1 [ 64]. Увеличение содержания B. thetaiotaomicron может быть следствием инициирования при КРР одного из защитных механизмов организма, направленных на разрушение опухолевой ткани и стабилизации кишечного барьера.…”

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“…Still, B. fragilis plays an intricate role in a way that enterotoxigenic B. fragilis-derived toxins induced Diarrhea, inflammatory bowel disease (IBD) and CRC, while non-toxigenic B.fragilis (NTBF) promoted mucosal immune development or suppress colitis and inflammation-associated CRC (Chan et al, 2019;Ryu et al, 2020). NTBF also has a beneficial relationship with the host through modulation of the host's immune response by secreting outer membrane vesicles (OMVs) containing polysaccharide A (PSA).…”

“…Besides, some Bacteroides spp. like Bacteroides thetaiotaomicron (BT) ferment comestible fibers into some short-chain fatty acids (SCFAs) like propionate that repressed several histone methyltransferases which were presumed to have a functional role in CRC growth and metastasis (Okugawa et al, 2015;Ryu et al, 2020). SCFAs can also suppress the expression of proinflammatory cytokines and decrease colonic inflammation in colitis-associated colorectal cancer model (Tian et al, 2018) and offers some protection against Salmonella (Jacobson et al, 2018).…”

Bacteroides fragilis Induce Apoptosis and subG1/G1 Arrest Via Caspase and Nrf2 Signaling Pathways in HT-29 Cell Line

“…Still, B. fragilis plays an intricate role in a way that enterotoxigenic B. fragilis-derived toxins induced Diarrhea, inflammatory bowel disease (IBD) and CRC, while non-toxigenic B.fragilis (NTBF) promoted mucosal immune development or suppress colitis and inflammation-associated CRC (Chan et al, 2019;Ryu et al, 2020). NTBF also has a beneficial relationship with the host through modulation of the host's immune response by secreting outer membrane vesicles (OMVs) containing polysaccharide A (PSA).…”

“…Besides, some Bacteroides spp. like Bacteroides thetaiotaomicron (BT) ferment comestible fibers into some short-chain fatty acids (SCFAs) like propionate that repressed several histone methyltransferases which were presumed to have a functional role in CRC growth and metastasis (Okugawa et al, 2015;Ryu et al, 2020). SCFAs can also suppress the expression of proinflammatory cytokines and decrease colonic inflammation in colitis-associated colorectal cancer model (Tian et al, 2018) and offers some protection against Salmonella (Jacobson et al, 2018).…”