Promoter demethylation of the asparagine synthetase gene is required for ATF4-dependent adaptation to asparagine depletion

Jiang, Jie; Srivastava, Sankalp; Seim, Gretchen; Pavlova, Natalya N.; King, Bryan; Zou, Lihua; Zhang, Chi; Zhong, Minghua; Feng, Hui; Kapur, Reuben; Wek, Ronald C.; Fan, Jianqing; Zhang, Ji

doi:10.1074/jbc.ra119.010447

Cited by 34 publications

(30 citation statements)

References 46 publications

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“…Although we could not explain at present through which signaling pathway ASNS promotes PNI, the amino acids metabolism alterations behind the nerve invasion of OSCC need be noticed. As reported, the activating transcription factor (ATF)-4 targeted ASNS and knockdown of ATF-4 significantly reduced ASNS expression (30)(31)(32). Moreover, induction of ATF-4 is dependent on the activation of the PI3K-AKT-mTOR signaling (31,33).…”

Section: Discussionmentioning

confidence: 69%

Asparagine Synthetase-Mediated l-Asparagine Metabolism Disorder Promotes the Perineural Invasion of Oral Squamous Cell Carcinoma

Ding

Yang

et al. 2021

Front. Oncol.

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Dysregulated amino acids metabolism reciprocally interplays with evolutionary phenotypic characteristics of cancer cells to enhance metastasis. The high metastasis potential of oral squamous cell carcinoma (OSCC) can manifest with perineural invasion (PNI). We here aimed to determine the role of amino acids metabolism in OSCCs with different PNI statuses. Targeted metabolomics was used to quantify 48 amino acids in 20 fresh OSCC samples and 25 amino acids were successfully detected, within which 9 were significantly up-regulated in PNI positive (PNI+) samples. As its highest area under the curve value (0.9063), l-asparagine was selected as the biomarker to distinguish PNI+ from PNI negative (PNI−). Then, the key enzyme of l-asparagine, asparagine synthetase (ASNS), was investigated using immunohistochemistry with 86 OSCC patients. The results showed that ASNS mainly expressed in tumor epitheliums and positively correlated with lymph node metastasis and PNI. Moreover, subgroup survival analysis revealed that ASNS expression combined with PNI status significantly improved their prognostic value, which was confirmed by the TCGA OSCC cohort (n = 279). To validate whether ASNS promotes PNI, we determined ASNS expression levels in five OSCC cell lines and one normal oral keratinocyte, and HSC3 showed the lowest ASNS level but CAL33 had the highest. Therefore, HSC3 and CAL33 (or PBS as control) were selected and injected separately into sciatic nerves to construct the in vivo PNI mouse models. Although both models eventually developed the hind-limb paralysis, nerve dysfunction in the CAL33 model progressed significantly earlier than HSC3 (Day 9 vs. Day 24). Besides, CAL33 migrated significantly farther than HSC3 in the nerve microenvironment (P = 0.0003), indicating high ASNS expression is indispensable for OSCC progression, especially PNI formation, through l-asparagine metabolism alteration. This study provides novel insights into how amino acids metabolism disorders alter tumor neurotropism which helps cancer metastasis.

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Section: Discussionmentioning

confidence: 69%

Asparagine Synthetase-Mediated l-Asparagine Metabolism Disorder Promotes the Perineural Invasion of Oral Squamous Cell Carcinoma

Ding

Yang

et al. 2021

Front. Oncol.

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“…tRNA Charging Assay. To examine rhythms in the levels of tRNA val , a tRNA charging assay was performed (85). Total RNA was extracted from ground tissue obtained from circadian time courses of WT (FGSC#4200) and un-3 ts (FGSC#81) strains.…”

Section: Methodsmentioning

confidence: 99%

Circadian clock control of eIF2α phosphorylation is necessary for rhythmic translation initiation

Karki

Castillo

Ding

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The circadian clock in eukaryotes controls transcriptional and posttranscriptional events, including regulation of the levels and phosphorylation state of translation factors. However, the mechanisms underlying clock control of translation initiation, and the impact of this potential regulation on rhythmic protein synthesis, were not known. We show that inhibitory phosphorylation of eIF2α (P-eIF2α), a conserved translation initiation factor, is clock controlled in Neurospora crassa, peaking during the subjective day. Cycling P-eIF2α levels required rhythmic activation of the eIF2α kinase CPC-3 (the homolog of yeast and mammalian GCN2), and rhythmic activation of CPC-3 was abolished under conditions in which the levels of charged tRNAs were altered. Clock-controlled accumulation of P-eIF2α led to reduced translation during the day in vitro and was necessary for the rhythmic synthesis of select proteins in vivo. Finally, loss of rhythmic P-eIF2α levels led to reduced linear growth rates, supporting the idea that partitioning translation to specific times of day provides a growth advantage to the organism. Together, these results reveal a fundamental mechanism by which the clock regulates rhythmic protein production, and provide key insights into how rhythmic translation, cellular energy, stress, and nutrient metabolism are linked through the levels of charged versus uncharged tRNAs.

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“…Possible translational control may explain the numerous clinical reports that showed no correlation between ASNS mRNA and ASNase sensitivity (24). Recently, Jiang et al have demonstrated that methylation status of the ASNS promoter is not the same in different ALL models and that hypermethylation inversely correlates not only with the basal ASNS expression but also with the capacity to trigger the ATF4-dependent increase in ASNS expression upon following Asn depletion (25). However, although, intuitively, ASNS induction has been correlated with resistance to ASNase, it has been known for many years that ASNase-resistant ALL cells present a complex phenotype.…”

Section: Low Asns Expression In Acute Lymphoblastic Leukemia: Old Obsmentioning

confidence: 99%

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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Promoter demethylation of the asparagine synthetase gene is required for ATF4-dependent adaptation to asparagine depletion

Cited by 34 publications

References 46 publications

Asparagine Synthetase-Mediated l-Asparagine Metabolism Disorder Promotes the Perineural Invasion of Oral Squamous Cell Carcinoma

Asparagine Synthetase-Mediated l-Asparagine Metabolism Disorder Promotes the Perineural Invasion of Oral Squamous Cell Carcinoma

Circadian clock control of eIF2α phosphorylation is necessary for rhythmic translation initiation

Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia

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