Colonic Lysine Homocysteinylation Induced by High-Fat Diet Suppresses DNA Damage Repair

Wang, Dan; Zhao, Rui; Qu, Yuanyuan; Mei, Xinyu; Zhang, Xuan; Zhou, Qian; Li, Yang; Yang, Shaobo; Zuo, Zhili; Chen, Yiming; Lin, Yan; Xu, Wei; Chen, Chao; Zhao, Shimin; Zhao, Jin

doi:10.1016/j.celrep.2018.09.022

Cited by 79 publications

(84 citation statements)

References 49 publications

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“…Zhang et al [6] treated NE4C cells with 0.1, 0.5, and 1 mM Hcy, and found that the pathological effects of Hcy were in a dose-dependent manner. In our previous study of DNA damage model induced by hydroxyurea, we have observed that supplementing the cell-culture media with 0.5 mM Hcy aggravated the number of damaged cells in HCT116 cells [35]. Therefore, we used 0.5 mM Hcy to observe its effects on accumulation of DNA damage and promotion of cytotoxicity in NE4C cells under conditions of MMCinduced DNA damage in this study.…”

Section: Discussionmentioning

confidence: 96%

“…Previous studies have been shown that Hcy can sensitize cells to DNA damage agents [15,35]; however, the precise mechanism by which Hcy exacerbates DNA damage in neural cells is not fully discovered. Mitomycin C (MMC), a common chemotherapeutic drug for many malignancies, inhibits cell proliferation and causes death by inducing ICLs [36][37][38].…”

Section: Ivyspringmentioning

confidence: 99%

“…Murine NE4C neural stem cells (ATCC ® CRL-2925 ™ ) were maintained in Minimum Essential Medium (MEM; Gibco, Carlsbad, CA, USA) with 10% fetal bovine serum, 2 mM glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin. The NE4C cells were treated with saline (control), 0.1 μM MMC (Sigma-Aldrich, St Louis, MO, USA), or a combination of 0.1 μM MMC and 0.5 mM Hcy (Sigma-Aldrich) for 24 h as previously described (35). MMC and Hcy were dissolved in saline.…”

Section: Cell Culture Treatment and Transfectionmentioning

confidence: 99%

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Homocysteine aggravates DNA damage by impairing the FA/Brca1 Pathway in NE4C murine neural stem cells

et al. 2020

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There is existing evidence that elevated homocysteine (Hcy) levels are risk factors for some neurodegenerative disorders. The pathogenesis of neurological diseases could be contributed to excessive cell dysfunction and death caused by defective DNA damage response (DDR) and accumulated DNA damage. Hcy is a neurotoxic amino acid and acts as a DNA damage inducer. However, it is not clear whether Hcy participates in the DDR. To investigate the effects of Hcy on DNA damage and the DDR, we employed mitomycin C (MMC) to cause DNA damage in NE4C murine neural stem cells (NSCs). Compared to treatment with MMC alone, we found that co-treatment with MMC and Hcy worsened DNA damage and increased death in NE4C cells. Intriguingly, in this DNA damage model mimicked by MMC, immunoblotting results showed that the monoubiquitination levels of Fanconi anemia complementation group I (Fanci) and Fanconi anemia complementation group D2 (Fancd2) were decreased to about 60.3% and 55.7% by supplementing cell culture medium with Hcy, indicating Hcy inactivates the function of Fanci and Fancd2 in DNA damage conditions. Given Breast Cancer 1 (BRCA1) is an important downstream of FANCD2, we next detected the interaction between Fancd2 and Brca1 in NE4C cells. Compared to treatment with MMC alone, the Fancd2-Brca1 interaction and the amount of Brca1 on chromatin were decreased when cells were co-exposed to MMC and Hcy, suggesting Hcy could impair the Fanconi anemia (FA)/Brca1 pathway. Taken together, our study demonstrates that Hcy may enhance cell death, which contributes to the accumulation of DNA damage and promotion of hypersensitivity to cytotoxicity by impairing the FA/Brca1 pathway in murine NSCs in the presence of DNA damage.

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Section: Discussionmentioning

confidence: 96%

Section: Ivyspringmentioning

confidence: 99%

Section: Cell Culture Treatment and Transfectionmentioning

confidence: 99%

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Homocysteine aggravates DNA damage by impairing the FA/Brca1 Pathway in NE4C murine neural stem cells

et al. 2020

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“…Mounting epidemiological evidence indicates that HFDs, rich in carbohydrates and saturated fatty acids, are an acknowledged risk factor for CRC 42 . HFDs lead to commensurate increases in fecal bile acids, particularly lithocholic and deoxycholic acids, which are potent inducers of CRC 43 .…”

Section: Discussionmentioning

confidence: 99%

Farnesoid X receptor antagonizes Wnt/β-catenin signaling in colorectal tumorigenesis

Guo

et al. 2020

Cell Death Dis

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Farnesoid X receptor (FXR, encoded by NR1H4), a critical regulator of bile acid homeostasis, is widely implicated in human tumorigenesis. However, the functional role of FXR in colorectal cancer (CRC) and the precise molecular mechanism remain unclear. In this study, we demonstrated that FXR expression was downregulated in colon cancer tissues and decreased expression of FXR predicted a poor prognosis. Knockdown of FXR promoted colon cancer cell growth and invasion in vitro, and facilitated xenograft tumor formation and distant metastasis in vivo, whereas ectopic expression of FXR had the reserved change. Mechanistic studies indicated that FXR exerted its tumor suppressor functions by antagonizing Wnt/β-catenin signaling. Furthermore, we identified an FXR/β-catenin interaction in colon cancer cells. The FXR/β-catenin interaction impaired β-catenin/TCF4 complex formation. In addition, our study suggested a reciprocal relationship between FXR and β-catenin, since loss of β-catenin increased the transcriptional activation of SHP by FXR. Altogether, these data indicated that FXR functions a tumor-suppressor role in CRC by antagonizing Wnt/β-catenin signaling.

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“…Moreover, certain ARSs and AIMPs could regulate tumorigenesis by p53 ( Park et al, 2005 ; Choi et al, 2011 ; Wang et al, 2018 ). High-fat diet induced colonic lysine homocysteinylation through MRS, which led to the accumulation of DNA damage and colorectal cancer-like phenotypes in the colon of mice and rats ( Wang et al, 2018 ).…”

Section: Roles Of Arss In Cancermentioning

confidence: 99%

Roles of Aminoacyl-tRNA Synthetases in Cancer

Zhou

Sun

Nie

et al. 2020

Front. Cell Dev. Biol.

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Aminoacyl-tRNA synthetases (ARSs) catalyze the ligation of amino acids to their cognate transfer RNAs (tRNAs), thus playing an important role in protein synthesis. In eukaryotic cells, these enzymes exist in free form or in the form of multi-tRNA synthetase complex (MSC). The latter contains nine cytoplasmic ARSs and three ARS-interacting multifunctional proteins (AIMPs). Normally, ARSs and AIMPs are regarded as housekeeping molecules without additional functions. However, a growing number of studies indicate that ARSs are involved in a variety of physiological and pathological processes, especially tumorigenesis. Here, we introduce the roles of ARSs and AIMPs in certain cancers, such as colon cancer, lung cancer, breast cancer, gastric cancer and pancreatic cancer. Furthermore, we particularly focus on their potential clinical applications in cancer, aiming at providing new insights into the pathogenesis and treatment of cancer.

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Colonic Lysine Homocysteinylation Induced by High-Fat Diet Suppresses DNA Damage Repair

Abstract: Highlights d High-fat diet induces colonic lysine homocysteinylation (K-Hcy) catalyzed by MARS d Increased MARS copy number is a risk factor for human colorectal cancer (CRC) d K-Hcy impedes DNA damage repair in CRC d K-Hcy inhibition decreases high-fat-induced oncogenic effects

Cited by 79 publications

References 49 publications

Homocysteine aggravates DNA damage by impairing the FA/Brca1 Pathway in NE4C murine neural stem cells

Homocysteine aggravates DNA damage by impairing the FA/Brca1 Pathway in NE4C murine neural stem cells

Farnesoid X receptor antagonizes Wnt/β-catenin signaling in colorectal tumorigenesis

Roles of Aminoacyl-tRNA Synthetases in Cancer

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