NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells

Zhao, Di; Mo, Yan; Li, Meng Tian; Zou, Shao Wu; Cheng, Zhou Li; Sun, Yi; Xiong, Yue; Guan, Kun Liang; Lei, Qun-Ying

doi:10.1172/jci76611

Cited by 141 publications

(125 citation statements)

References 41 publications

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“…Increased expression of hypoxia-inducible factors 1 and 2α was also shown to be associated with ALDH1 activity and believed to raise the metastatic propensity of ALDH1 high cells (6,47,48). Furthermore, increased expression of homeobox A1 and mucin 4 were associated with high ALDH1 activity, also contributing to tumor relapse and metastasis.…”

Section: Aldh1mentioning

confidence: 96%

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

Paula

Lopes

2017

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Section: Aldh1mentioning

confidence: 96%

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

Paula

Lopes

2017

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“…For example, the M2 isoform of pyruvate kinase (PKM2) is acetylated at lysine residue 433 (K433), which promotes its nuclear accumulation and protein kinase activity to facilitate cell proliferation and tumorigenesis (16). In another instance, acetylation of aldehyde dehydrogenase (ALDH) inhibits its enzyme activity, thereby suppressing breast cancer stem cells (17). Considering the importance of lysine acetylation in the regulation of metabolism, dissecting the function and regulatory mechanism of the acetylation of metabolic enzymes is instrumental in our fight against metabolic disorders, such as cancer, diabetes, and fatty liver disease.…”

mentioning

confidence: 99%

Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

Guo

Zhou

Wei

et al. 2016

Molecular and Cellular Biology

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bNonalcoholic fatty liver disease (NAFLD) has become the most common liver disease, and decreased fatty acid oxidation is one of the important contributors to NAFLD. Mitochondrial trifunctional protein ␣-subunit (MTP␣) functions as a critical enzyme for fatty acid ␤-oxidation, but whether dysregulation of MTP␣ is pathogenically connected to NAFLD is poorly understood. We show that MTP␣ is acetylated at lysine residues 350, 383, and 406 (MTP␣-3K), which promotes its protein stability by antagonizing its ubiquitylation on the same three lysines (MTP␣-3K) and blocking its subsequent degradation. Sirtuin 4 (SIRT4) has been identified as the deacetylase, deacetylating and destabilizing MTP␣. Replacement of MTP␣-3K with either MTP␣-3KR or MTP␣-3KQ inhibits cellular lipid accumulation both in free fatty acid (FFA)-treated alpha mouse liver 12 (AML12) cells and primary hepatocytes and in the livers of high-fat/high-sucrose (HF/HS) diet-fed mice. Moreover, knockdown of SIRT4 could phenocopy the effects of MTP␣-3K mutant expression in mouse livers, and MTP␣-3K mutants more efficiently attenuate SIRT4-mediated hepatic steatosis in HF/HS diet-fed mice. Importantly, acetylation of both MTP␣ and MTP␣-3K is decreased while SIRT4 is increased in the livers of mice and humans with NAFLD. Our study reveals a novel mechanism of MTP␣ regulation by acetylation and ubiquitylation and a direct functional link of this regulation to NAFLD.

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“…2 Another important property of CSCs is that they are believed to be the cell sources developing drug resistance due to high expression levels of specific ABC drug transporters. 3 CD133 is a widely accepted bio-marker for tumor-initiating cells in various cancer types including EC and CD133C cells exhibited significant resistance to chemotherapy. 4 Studies indicate that activation of NOTCH signaling pathway is a common event in CD133C cells and inactivating NOTCH pathway can sensitize CD133C cells to chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

“…4 Studies indicate that activation of NOTCH signaling pathway is a common event in CD133C cells and inactivating NOTCH pathway can sensitize CD133C cells to chemotherapy. 5 In mammals, NOTCH (1)(2)(3)(4) signals are activated through binding to 5 ligands (Jagged-1, -2, and Delta-like-1, -3, and -4), and this leads to sequential proteolytic cleavages and the nuclear translocation of the intracellular domains of Notch receptors (NICDs) that regulates downstream NOTCH-dependent transcription. Disordered NOTCH signaling can promote tumorigenesis in variant types of cancers by increasing cancer stem cell activities.…”

Section: Introductionmentioning

confidence: 99%

Blocking NOTCH pathway can enhance the effect of EGFR inhibitor through targeting CD133+ endometrial cancer cells

Shang

Liu

2016

Cancer Biology & Therapy

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Although the molecular therapeutics targeting key biomarkers such as epithelial growth factor receptor (EGFR), PI3K/AKT/mTOR, and vascular endothelial growth factor (VEGF) shows some success in clinical trials, some internally existing challenges in endothelial cancer biology hinder the drug effects. One of the major challenges stems from cancer stem cell-derived drug resistance. CD133 positive cells are well believed as cancer stem cells (CSC) in endometrial cancers and NOTCH pathway plays a critical role in retaining CD133C cells by promoting CSC self-renewal and chemoresistance. Here, we initiated a therapeutic strategy to improve effects of EGFR inhibition by targeting NOTCH pathway of CD133C cells in endometrial cancers. We first detected and purified the CD133C cell fraction in endometrial cancer cell line Ishikawa (IK), and validated activation of NOTCH pathway in the CD133C cells that have higher proliferation rate and lower apoptosis rate, comparing to CD133-cells. Results of nude mouse xenograft experiments further demonstrated CD133C cells retain higher tumorigenesis capacity than CD133-cells, indicating their tumorinitiating property. Last, we applied both NOTCH inhibitor DAPT and EGFR inhibitor AG1478 treatment on endometrial cancer lines IK and HEC-1A and the results suggested improvement effects of the combination therapy compared to the treatments of DAPT or AG1478 alone. These findings indicated targeting NOTCH pathway in CD133C cells, combining with EGFR inhibition, which provides a novel therapeutic strategy for endometrial cancer diseases.

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NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells

Cited by 141 publications

References 41 publications

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

Acetylation of Mitochondrial Trifunctional Protein α-Subunit Enhances Its Stability To Promote Fatty Acid Oxidation and Is Decreased in Nonalcoholic Fatty Liver Disease

Blocking NOTCH pathway can enhance the effect of EGFR inhibitor through targeting CD133+ endometrial cancer cells

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