Down‐Regulation of Asparagine Synthetase Induces Cell Cycle Arrest and Inhibits Cell Proliferation of Breast Cancer

Yang, Hongjian; He, Xiangming; Zheng, Yabing; Feng, Wenjie; Xia, Xianghou; Yu, Xiao Fang; Lin, Zhiqiang

doi:10.1111/cbdd.12348

Cited by 33 publications

(23 citation statements)

References 27 publications

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“…FOXM1 protein is the most significantly upregulated protein and/or antigen in USP21 -amplified tumors (Figure 4D). Among the other most statistically significant increasing proteins were the FOXM1 targets cyclin B1, the cell cycle-regulated gene MSH6 (Fischer et al, 2016), adenosine deaminase ADAR1 (which is proximal to the genetic location of USP21), and the asparagine deaminase ASNS, which has been previously implicated in breast cancer proliferation and cell cycle progression (Yang et al, 2014). Because FOXM1 is upregulated by USP21, we asked whether a curated list of 114 FOXM1 target genes is correlated with USP21 amplification using gene set enrichment analysis (GSEA).…”

Section: Resultsmentioning

confidence: 99%

FOXM1 Deubiquitination by USP21 Regulates Cell Cycle Progression and Paclitaxel Sensitivity in Basal-like Breast Cancer

et al. 2019

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SUMMARYThe transcription factor FOXM1 contributes to cell cycle progression and is significantly upregulated in basal-like breast cancer (BLBC). Despite its importance in normal and cancer cell cycles, we lack a complete understanding of mechanisms that regulate FOXM1. We identified USP21 in an RNAi-based screen for deubiquitinases that control FOXM1 abundance. USP21 increases the stability of FOXM1, and USP21 binds and deubiquitinates FOXM1 in vivo and in vitro, indicating a direct enzyme-substrate relationship. Depleting USP21 downregulates the FOXM1 transcriptional network and causes a signifi-cant delay in cell cycle progression. Significantly, USP21 depletion sensitized BLBC cell lines and mouse xenograft tumors to paclitaxel, an anti-mitotic, frontline therapy in BLBC treatment. USP21 is the most frequently amplified deubiquitinase in BLBC patient tumors, and its amplification co-occurs with the upregulation of FOXM1 protein. Altogether, these data suggest a role for USP21 in the proliferation and potentially treatment of FOXM1-high, USP21-high BLBC.

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Section: Resultsmentioning

confidence: 99%

FOXM1 Deubiquitination by USP21 Regulates Cell Cycle Progression and Paclitaxel Sensitivity in Basal-like Breast Cancer

et al. 2019

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“…In breast cancer cells, ASNS is a target of IGF1/IGF2dependent anabolic signaling (59), and, consistently, ASNS silencing depressed cell proliferation in two distinct cell lines, one of which derives from a triple negative tumor (60). Moreover, ASNS expression and Asn availability have been found to be strongly correlated with the metastatic behavior of breast cancer (61).…”

Section: High Asns Expression In Cancer: a Pro-tumor Enzyme?mentioning

confidence: 90%

Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia

et al. 2020

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Asparagine Synthetase (ASNS) catalyzes the synthesis of the non-essential amino acid asparagine (Asn) from aspartate (Asp) and glutamine (Gln). ASNS expression is highly regulated at the transcriptional level, being induced by both the Amino Acid Response (AAR) and the Unfolded Protein Response (UPR) pathways. Lack of ASNS protein expression is a hallmark of Acute Lymphoblastic Leukemia (ALL) blasts, which, therefore, are auxotrophic for Asn. This peculiarity is the rationale for the use of bacterial L-Asparaginase (ASNase) for ALL therapy, the first example of anti-cancer treatment targeting a tumor-specific metabolic feature. Other hematological and solid cancers express low levels of ASNS and, therefore, should also be Asn auxotrophs and ASNase sensitive. Conversely, in the last few years, several reports indicate that in some cancer types ASNS is overexpressed, promoting cell proliferation, chemoresistance, and a metastatic behavior. However, enhanced ASNS activity may constitute a metabolic vulnerability in selected cancer models, suggesting a variable and tumor-specific role of the enzyme in cancer. Recent evidence indicates that, beyond its canonical role in protein synthesis, Asn may have additional regulatory functions. These observations prompt a re-appreciation of ASNS activity in the biology of normal and cancer tissues, with particular attention to the fueling of Asn exchange between cancer cells and the tumor microenvironment.

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“…These results indicated that ASNS may be directly involved in cell cycle control and contribute to cancer cell growth as an oncogene. This is supported by a recent report showing that depletion of ASNS potently inhibited the proliferation of ZR‐75‐30 and MDA‐MB‐231 breast cancer cells via S phase cell cycle arrest . However, a functional study in human HCC cells showed different results, in which, ectopic expression of ASNS gene strongly decreased the proliferation and migration and knockdown of ASNS markedly increased sensitivity to l ‐asparaginase .…”

Section: Discussionmentioning

confidence: 53%

Knockdown of asparagine synthetase by RNAi suppresses cell growth in human melanoma cells and epidermoid carcinoma cells

Zhou

et al. 2015

Biotech and App Biochem

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Melanoma, the most aggressive form of skin cancer, causes more than 40,000 deaths each year worldwide. And epidermoid carcinoma is another major form of skin cancer, which could be studied together with melanoma in several aspects. Asparagine synthetase (ASNS) gene encodes an enzyme that catalyzes the glutamine- and ATP-dependent conversion of aspartic acid to asparagine, and its expression is associated with the chemotherapy resistance and prognosis in several human cancers. The present study aims to explore the potential role of ASNS in melanoma cells A375 and human epidermoid carcinoma cell line A431. We applied a lentivirus-mediated RNA interference (RNAi) system to study its function in cell growth of both cells. The results revealed that inhibition of ASNS expression by RNAi significantly suppressed the growth of melanoma cells and epidermoid carcinoma cells, and induced a G0/G1 cell cycle arrest in melanoma cells. Knockdown of ASNS in A375 cells remarkably downregulated the expression levels of CDK4, CDK6, and Cyclin D1, and upregulated the expression of p21. Therefore, our study provides evidence that ASNS may represent a potential therapeutic target for the treatment of melanoma.

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Down‐Regulation of Asparagine Synthetase Induces Cell Cycle Arrest and Inhibits Cell Proliferation of Breast Cancer

Cited by 33 publications

References 27 publications

FOXM1 Deubiquitination by USP21 Regulates Cell Cycle Progression and Paclitaxel Sensitivity in Basal-like Breast Cancer

FOXM1 Deubiquitination by USP21 Regulates Cell Cycle Progression and Paclitaxel Sensitivity in Basal-like Breast Cancer

Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia

Knockdown of asparagine synthetase by RNAi suppresses cell growth in human melanoma cells and epidermoid carcinoma cells

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