Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer

Zurlo, Giada; Liu, Xijuan; Takada, Mamoru; Fan, Cheng; Simon, Jeremy M.; Ptacek, Travis; Rodríguez, Javier; Kriegsheim, Alex von; Liu, Juan; Locasale, Jason W.; Robinson, Andrea; Zhang, Jing; Holler, Jessica; Kim, Baek; Zikánová, Marie; Bierau, Jörgen; Xie, Ling; Chen, Xian; Li, Mingjie; Perou, Charles M.; Zhang, Qing

doi:10.1038/s41467-019-13168-4

Cited by 32 publications

(42 citation statements)

References 50 publications

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“…Luminal A and Luminal B share similarities in prognosis, while Luminal B have lower expression of hormone receptors, higher expression of proliferation markers, and higher histologic grade than luminal A [17, 18]. Triple-negative breast cancer is defined by aggressive clinical behavior and occurs in 10–15% of sporadic breast cancers [19, 20]. There were 19 (20.21%) TNBC molecular typing patients carried p.Ile1845fs variant.…”

Section: Discussionmentioning

confidence: 99%

Profiling of the germline mutation BRCA1: p.Ile1845fs in a large cohort of Han Chinese breast cancer

Zhang²,

Weng

et al. 2019

Hereditas

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BackgroundBreast cancer is a one of the malignant carcinomas partially caused by genetic risk factors. Germline BRCA1 gene mutations are reportedly associated with breast cancers. Identification of BRCA1 mutations greatly improves the preventive strategies and management of breast cancer. The aim of our study was to investigate the frequency of the deleterious BRCA1: p.Ile1845fs variant in breast carcinomas, as well as the correlation between p.Ile1845fs variant with clinicopathological parameters and clinical outcomes.ResultsA total of 23,481 clinically high-risk patients with breast cancer and 6489 healthy controls were recruited for p.Ile1845fs variant sequencing (either sanger or next generation sequencing). We identified 94 breast cancer patients (0.40%, 94/23481) as well as 11 healthy controls (0.17%, 11/6489) carried p.Ile1845fs variant. BRCA1: p.Ile1845fs variant showed a higher frequency in patients with TNBC molecular typing (20.21%, 19/94) and family history (37.23%, 35/94) compared with non-carriers (P = 3.62E-6 and 0.034, respectively). According to our data, we advanced the frequency of p.Ile1845fs variant and we confirmed that BRCA1: p.Ile1845fs variant was associated with increased risk of breast cancer (OR = 2.36, 95%CI = 1.26–4.89, P = 0.004).ConclusionsBRCA1: p.Ile1845fs variant was a frequently pathogenic mutation in breast cancer in Han Chinese women and our data may be helpful for diagnosis and therapy of breast cancer.

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Section: Discussionmentioning

confidence: 99%

Profiling of the germline mutation BRCA1: p.Ile1845fs in a large cohort of Han Chinese breast cancer

Zhang²,

Weng

et al. 2019

Hereditas

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“…DEC2 sgRNA plasmid and lentivirus are constructed as previously described [ 22 ]. Target sequences were as follows:…”

Section: Methodsmentioning

confidence: 99%

DEC2 Serves as Potential Tumor Suppressor in Breast Carcinoma

Fang

Wang

et al. 2020

Disease Markers

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Background. Identification of new biomarkers can facilitate the development of effective therapeutic strategies in breast cancer (BC). Data from previous studies have revealed that differentiated embryonic chondrocyte gene (DEC) 1 and DEC2 might involve in the progression of various cancer types. We explored the expression profiles and function of DEC1/2 in BC patients in this study. Methods. The mRNA expression of DEC1/2 in BC patients and cell lines were taken from the Oncomine and Cancer Cell Line Encyclopedia database. The prognostic impacts of DEC1/2 were mined from the bc-GenExMiner and Kaplan–Meier plotter database. The impact of DEC1/2 genomic alterations on patient survival was calculated by cBioPortal. DEC2 protein expressions were confirmed by Western blotting (WB) in 10 pairs of BC samples. In addition, DEC2 sgRNA was constructed to confirm its affection on cell viability, invasion, and colony formation. Results. The DEC1 and DEC2 mRNA levels are both lower in BC tissues than normal tissues. DEC1/2 expression was high in progesterone receptor (PR) positive BC patients (P=0.0023), but low in human epidermal growth factor receptor 2 (HER2) positive patients (P<0.0001). Lower DEC2 mRNA level has significant association with more aggressive pathogenic grade (P<0.0001) and worse overall survival (OS) of BC patients (P=5.2×10−6). Subgroup analysis showed that low DEC2 level was correlated with worse OS in estrogen receptor (ER) positive BC (P=0.008). DEC2 (P=0.00029) alteration was significantly correlated with worse OS in BC patients. WB results also confirmed the lower DEC2 protein levels in BC samples than their paired normal tissues. And, DEC2 silencing by sgRNA resulted in a significant increasing in cell viability, invasion, and colony formation. Conclusion. DEC2 might serve as a tumor suppressor, and its disfunction may involve in the tumorigenesis and indicate bad clinical outcomes in BC patients.

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“…In recent years, non-HIF targets have been identified to be hydroxylated on prolines by PHDs (reviewed in [ 15 ]), resulting in their degradation and/or changes to downstream activity including Centrosomal Protein 192 (CEP192) [ 272 ], Forkhead Box O3 (FOXO3) [ 273 ] and Adenylosuccinate Lyase (ADSL) [ 274 ] by PHD1, Actin Beta (ACTB) by PHD3 [ 275 ], and AKT Serine/Threonine Kinase 1 (AKT1) [ 93 ], TANK Binding Kinase 1 (TBK1) [ 276 ] and Scm-like with Four Malignant Brain Tumour Domains 1 (SFMBT1) [ 277 ] by PHD2 [ 278 ]. Despite these exciting studies, a recent study investigating around 20 of the reported non-HIF substrates, failed to detect any hydroxylation in vitro [ 279 ].…”

Section: Effects Of Hypoxia On Protein Levelsmentioning

confidence: 99%

Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia

Frost

Batie

et al. 2021

Cancers

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Hypoxia—reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation. We highlight the relevance of HIF and 2-OGDs in the control of gene expression in response to hypoxia and their relevance to human biology and health.

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Prolyl hydroxylase substrate adenylosuccinate lyase is an oncogenic driver in triple negative breast cancer

Cited by 32 publications

References 50 publications

Profiling of the germline mutation BRCA1: p.Ile1845fs in a large cohort of Han Chinese breast cancer

Profiling of the germline mutation BRCA1: p.Ile1845fs in a large cohort of Han Chinese breast cancer

DEC2 Serves as Potential Tumor Suppressor in Breast Carcinoma

Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia

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