CHAF1A Blocks Neuronal Differentiation and Promotes Neuroblastoma Oncogenesis via Metabolic Reprogramming

Tao, Ling; Moreno‐Smith, Myrthala; Ibarra‐García‐Padilla, Rodrigo; Milazzo, Giorgio; Drolet, Nathan A.; Hernandez, Blanca E; Oh, Yung-Hwan; Patel, Ivanshi; Kim, Jean J.; Zorman, Barry; Patel, Tajhal; Kamal, Abu Hena Mostafa; Zhao, Yanling; Hicks, John; Vasudevan, Sanjeev A.; Putluri, Nagireddy; Coarfa, Cristian; Sumazin, Pavel; Perini, Giovanni; Parchem, Ronald J.; Uribe, Rosa A.; Barbieri, Eveline

doi:10.1002/advs.202005047

Cited by 21 publications

(24 citation statements)

References 86 publications

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“…This was consistent with the research nding that elevated expression of CHAF1A could promote thymidylate synthetase activity, leading to 5-FU resistance in gastric cancer [43]. In addition, it was reported that abnormally high expression of CHAF1A could affect the metabolic pathways of some amino acids, such as methionine, eventually inducing 5'-methylthioadenosine (MTA) accumulation in neuroblastoma [7]. Homozygous deletion of the methylthioadenosine phosphorylase (MTAP) is frequently found in human cancers, and the application of purine analogue has been shown to be effective therapeutic option in MTAP deletion cancer patients [44].…”

Section: Discussionsupporting

confidence: 90%

“…The frequency of genetic alterations was too low to lead cancers development and progression. Elevated expression of CHAF1A has been reported to be associated with several solid cancers [4,6,7,11,34], it was found that this phenomenon was commonly shared in more cancer types, indicating that abnormal higher expression of CHAF1A could be a potential biomarker for cancer diagnosis. Moreover, there was no study about the functional roles and mechanisms of CHAF1A in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…CAF-1 is a nuclear complex containing three subunits in human cells, CHAF1A (p150), CHAF1B (p60), and RBBP4 (p48) [5]. Among the three subunits, CHAF1A is the major one and plays essential role in CAF-1 complex [6,7]. It is shown that cells were not in S phase when Chaf1a failed to bind to mouse heterochromatin-binding protein-1 (Hp1) during mitosis [8].…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of CHAF1A correlates with poor prognosis and tumor immunosuppressive microenvironment and resistance to treatment in cancer

Sun

et al. 2022

Preprint

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Background: As distinct marker of proliferating cells, chromatin assembly factor-1 (CAF-1) was critical in DNA replication. CHAF1A, the major subunit in CAF-1 complex, has been shown to be highly expressed in some cancer types. However, there is paucity information about the clinical significance, molecule functions and co-expressed gene network of CHAF1A in breast cancer. Methods: Bioinformatic analysis of CHAF1A and its co-expression gene network were performed using various public databases. Results: Abnormally high expression of CHAF1A was found in 20 types of cancer tissues. Elevated expression of CHAF1A was positively correlated with breast cancer progression and poor patient outcome. Co-expression gene network analysis indicated that CHAF1A was associated with not only cell proliferation, DNA repair, apoptosis, but also cancer metabolism, immune system, drug resistance and so on. More importantly, higher expression of CHAF1A was positively correlated with immunosuppressive microenvironment and resistance to endocrine therapy and chemotherapy. Conclusions: The current study indicates that elevated expression of CHAF1A can be used as diagnosis and poor prognosis biomarker of breast cancer. Although higher expression of CHAF1A induced fast resistance to endocrine therapy and chemotherapy, it may be a potential therapeutic target and biomarker to predict the sensitivity of immunotherapy in breast cancer patients.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Overexpression of CHAF1A correlates with poor prognosis and tumor immunosuppressive microenvironment and resistance to treatment in cancer

Sun

et al. 2022

Preprint

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“…Shen et al also demonstrated that CHAF1A overexpression facilitates cell proliferation, and inhibits apoptosis in human retinoblastoma cells [ 21 ]. Tao et al found that CHAF1A facilitates neuroblastoma oncogenesis and blocks neuronal differentiation through metabolic reprogramming [ 22 ]. Moreover, high levels of CHAF1A expression was found in GC tissue and cell lines, and the up-regulation of CHAF1A was found to be associated with poor clinical outcome [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

High CHAF1A Expression Levels Are Positively-Correlated with PD-L1 Expression and Indicate Poor Prognosis in Gastric Cancer

Bao

Zhang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Objective. The aim of this study was to analyze the association between the expression of chromatin assembly factor 1 subunit A (CHAF1A) in gastric cancer (GC) and clinicopathological features, disease prognosis, and expression of programmed cell death-ligand 1 (PD-L1). Material and Methods. A total of 140 GC tissue specimens were collected between January 2013 and December 2017. CHAF1A expression in GC and paracancerous tissues was determined. Then, the associations between CHAF1A expression level in the collected tissues and clinicopathological features as well as PD-L1 expression level were investigated. Cox regression analyses were carried out to determine whether CHAF1A is an independent prognostic factor for GC. Finally, the association between CHAF1A expression levels and survival of the GC patients was investigated. Results. A significantly higher level of CHAF1A expression in GC tissues was found compared to that in paracancerous tissues ( p = 0.042 ). CHAF1A expression level in GC tissues was found to be strongly associated with family history ( p = 0.005 ), smoking history ( p = 0.016 ), T stage ( p = 0.001 ), tumor marker AFP ( p = 0.017 ), tumor marker CEA ( p = 0.027 ), and PD-L1 expression ( p = 0.029 ). CHAF1A expression was also found to be positively correlated to PD-L1 expression ( p = 0.012 ). Moreover, high CHAF1A expression levels were found to lead to poor prognosis ( p = 0.019 ). Univariate and multivariate analyses all showed that CHAF1A was an independent poorer prognostic factor for gastric cancer ( p = 0.021 , HR = 1.175, 95% CI: 1.090–2.890 for univariate analyses; p = 0.014 , HR = 2.191, 95% CI:1.170–4.105 for multivariate analyses). A high level of CHAF1A expression was thus found to be an independent risk factor for GC prognosis. Conclusion. High CHAF1A expression is associated with poor GC prognosis and positively correlated to PD-L1 expression. Thus, CHAF1A expression level may be used as a novel biomarker for GC diagnosis.

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“…Polyamines, including spermidine, spermine, and their precursor putrescine, are tightly regulated polycationic molecules that are broadly involved in cellular activities (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.158457DS1) (1)(2)(3). Polyamine metabolic dysregulation has been intensively investigated in pathological conditions, including aging, cancers, and neurological and immunological diseases (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Gene mutations of polyamine pathway enzymes cause severe diseases (18)(19)(20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Phenylbutyrate modulates polyamine acetylase and ameliorates Snyder-Robinson syndrome in a Drosophila model and patient cells

Tao¹,

Diaz-Perez²,

Yu³

et al. 2022

JCI Insight

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Polyamine dysregulation plays key roles in a broad range of human diseases from cancer to neurodegeneration. Snyder-Robinson syndrome (SRS) is the first known genetic disorder of the polyamine pathway, caused by X-linked recessive loss-of-function mutations in spermine synthase. In the Drosophila SRS model, altered spermidine/spermine balance has been associated with increased generation of ROS and aldehydes, consistent with elevated spermidine catabolism. These toxic byproducts cause mitochondrial and lysosomal dysfunction, which are also observed in cells from SRS patients. No efficient therapy is available. We explored the biochemical mechanism and discovered acetyl-CoA reduction and altered protein acetylation as potentially novel pathomechanisms of SRS. We repurposed the FDA-approved drug phenylbutyrate (PBA) to treat SRS using an in vivo Drosophila model and patient fibroblast cell models. PBA treatment significantly restored the function of mitochondria and autolysosomes and extended life span in vivo in the Drosophila SRS model. Treating fibroblasts of patients with SRS with PBA ameliorated autolysosome dysfunction. We further explored the mechanism of drug action and found that PBA downregulates the first and rate-limiting spermidine catabolic enzyme spermidine/spermine N 1 -acetyltransferase 1 (SAT1), reduces the production of toxic metabolites, and inhibits the reduction of the substrate acetyl-CoA. Taken together, we revealed PBA as a potential modulator of SAT1 and acetyl-CoA levels and propose PBA as a therapy for SRS and potentially other polyamine dysregulation–related diseases.

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CHAF1A Blocks Neuronal Differentiation and Promotes Neuroblastoma Oncogenesis via Metabolic Reprogramming

Cited by 21 publications

References 86 publications

Overexpression of CHAF1A correlates with poor prognosis and tumor immunosuppressive microenvironment and resistance to treatment in cancer

Overexpression of CHAF1A correlates with poor prognosis and tumor immunosuppressive microenvironment and resistance to treatment in cancer

High CHAF1A Expression Levels Are Positively-Correlated with PD-L1 Expression and Indicate Poor Prognosis in Gastric Cancer

Phenylbutyrate modulates polyamine acetylase and ameliorates Snyder-Robinson syndrome in a Drosophila model and patient cells

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