Identification of circadian clock genes as regulators of immune infiltration in Hepatocellular Carcinoma

Zhang, Zhen; Liang, Zicheng; Gao, Wenhui; Shibata, Yu; Hou, Zongwei; Li, Kexin; Zeng, Puhua

doi:10.7150/jca.71925

Cited by 11 publications

(14 citation statements)

References 46 publications

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“…NPAS2 is a circadian clock gene and has been reported to be a crucial regulator of tumorigenesis and immune infiltration. NPAS2 was identified as an oncogene in hepatocellular carcinoma and was related to infiltration of immune cells [ 23 ]. In accordance with our findings, increased expression of NPAS2 has been suggested to indicate poor survival in lung cancer [ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma

et al. 2023

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Background Chromatin regulators (CRs) are critical epigenetic modifiers and have been reported to play critical roles during the progression of various tumors, but their role in lung adenocarcinoma (LUAD) has not been comprehensively studied. Methods Differential expression and univariate Cox regression analyses were conducted to identify the prognostic CRs. Consensus clustering was applied to classify the subtypes of LUAD based on prognostic CRs. LASSO-multivariate Cox regression method was used for construction of a prognostic signature and development of chromatin regulator-related gene index (CRGI). The capacity of CRGI to distinguish survival was evaluated via Kaplan–Meier method in multiple datasets. Relationship between CRGI and tumor microenvironment (TME) was evaluated. Additionally, clinical variables and CRGI were incorporated to create a nomogram. The role of the prognostic gene NPAS2 in LUAD was elucidated via clinical samples validation and a series of in vitro and in vivo experiments. Results Two subtypes of LUAD were classified based on 46 prognostic CRs via consensus clustering which had significantly different survival and TME. A prognostic signature consisting of six CRs (MOCS, PBK, CBX3, A1CF, NPAS2, and CTCFL) was developed and proved to be an effective survival predictor in multiple independent datasets. The prognostic signature was also demonstrated to be an indicator of TME and sensitivity to immunotherapy and chemotherapy. The nomogram was suggested to be a simple tool that can predict survival accurately. Clinical samples show that NPAS2 is highly expressed in LUAD tissues, and in vitro and in vivo experiments demonstrated that inhibition of NPAS2 impeded malignant progression of LUAD cells. Conclusions Our study comprehensively unveiled the functions of CRs in LUAD, developed a classifier to predict survival and response to treatments, and suggested that NPAS2 promoted LUAD progression for the first time.

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Section: Discussionmentioning

confidence: 99%

Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma

et al. 2023

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“…Accordingly, NPAS2 was comprised in a five-gene signature (DKK1, CCL20, NPAS2, GNPNAT1 and MELTF) predicting prognosis (decreased overall survival rates and shorter progression-free survival) and immunotherapy response of lung adenocarcinoma patients [76]. Likewise, higher expression of the NPAS2 gene in tumor tissue was closely related with immune infiltration and overall survival of glioma patients [77] as well as to immune infiltration and poor prognosis in hepatocellular carcinoma patients [78,79]. In the setting of hepatocellular carcinogenesis, upregulation of NPAS2 expression, chiefly attributable to the downregulation of miR-199b-5p, was found capable to reprogram glucose metabolism through transcriptional activation of HIF-1α with upregulation of the glycolytic genes GLUT1, HK2, GPI, ALDOA, ENO2, PKM2 and MCT4 and downregulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) with subsequent reduced mitochondrial biogenesis [80].…”

Section: Npas2 In Cancer Onset and Progressionmentioning

confidence: 99%

NPAS2, A Circadian Hemeprotein and Gas-Responsive Transcription Factor

Murgo,

Colangelo,

Bellet

et al. 2023

Preprint

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Neuronal PAS domain protein 2 (NPAS2) is a hemeprotein comprising a basic helix-loop-helix domain (bHLH) and two heme-binding sites, the PAS-A and PAS-B domains. This protein acts as a pyridine nucleotide-dependent and gas-responsive CO-dependent transcription factor and is encoded by a gene whose expression fluctuates with circadian rhythmicity. NPAS2 can heterodimerize with ARNTL in the activating limb of the transcriptional/translational feedback loop operating the circadian clock circuitry. NPAS2 can functionally substitute for the core transcription factor and histone/protein acetylase CLOCK in the molecular clockwork endowing central oscillators in the suprachiasmatic nuclei of hypothalamus as well as in peripheral oscillators in the cell of other body tissues, such as the liver and kidney.

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“…Neuronal PAS domain protein2 ( NPAS2 ; also called MOP4), the largest circadian gene located on chromosome 2 at 2q11.2, has received much attention in recent years because of its multiple biological functions and diverse roles in various diseases, particularly tumorigenesis 11 . NPAS2 was identified as an oncogene in hepatocellular carcinoma, uterine corpus endometrial carcinoma, acute myeloid leukaemia, etc., which was correlated with the biofunctional activities of NPAS2 in regulating cellular behaviours such as cell proliferation, migration and apoptosis 12–14 . Epidemiological studies have indicated that genetic variants in NPAS2 gene are significantly associated with overall survival of patients with NSCLC, and NPAS2 polymorphisms are suggested to serve as an independent prognostic marker for NSCLC patients 15 .…”

Section: Introductionmentioning

confidence: 99%

“…11 NPAS2 was identified as an oncogene in hepatocellular carcinoma, uterine corpus endometrial carcinoma, acute myeloid leukaemia, etc., which was correlated with the biofunctional activities of NPAS2 in regulating cellular behaviours such as cell proliferation, migration and apoptosis. [12][13][14] Epidemiological studies have indicated that genetic variants in NPAS2 gene are significantly associated with overall survival of patients with NSCLC, and NPAS2 polymorphisms are suggested to serve as an independent prognostic marker for NSCLC patients. 15 Importantly, a recent article published in April 2023 verified the high expression level of NPAS2 in tumour tissues of LUAD patients and confirmed the oncogenic role of NPAS2 in LUAD for the first time, preliminarily emphasizing the importance of NPAS2 in LUAD tumorigenesis and progression.…”

Section: Introductionmentioning

confidence: 99%

NPAS2, transcriptionally activated by ARRB1, promotes the malignant behaviours of lung adenocarcinoma cells and regulates the reprogramming of glucose metabolism

Wang,

Huang,

Zheng

et al. 2024

Clin Exp Pharma Physio

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Lung adenocarcinoma (LUAD) is a serious threat to public health and is accompanied by increased morbidity and mortality worldwide. Neuronal PAS domain protein2 (NPAS2) has been confirmed as an oncogene in LUAD; however, little is known about its molecular mechanism. Here, the expression level of NPAS2 was detected in LUAD cell lines and 16HBE cells. Gain‐ and loss‐of‐function experiments were performed. Cell Counting Kit‐8, colony formation, flow cytometry, wound‐healing and Transwell assays were conducted to assess cell proliferation, apoptosis, migration and invasion, respectively. Reprogramming of glucose metabolism was evaluated via oxygen consumption rate (OCR), complexes activities, lactic production and glucose consumption. The expression of critical proteins was examined by western blot. We demonstrated aberrant upregulation of NPAS2 and β‐arrestin‐1 (ARRB1) in LUAD cell lines. ARRB1 was found to be a critical transcription factor of NPAS2 with binding sites within the promoter region of NPAS2, thereby causing its transcriptional activation. Functional experiments revealed that NPAS2 depletion significantly inhibited the malignant behaviours of A549 cells by suppressing cell proliferation, migration, invasion and epithelial‐mesenchymal transition and promoting cell apoptosis. Meanwhile, NPAS2 depletion increased OCR and activities of complexes (I, II, III and V), and reduced lactic acid production and glucose uptake in A549 cells, indicating that NPAS2 depletion inhibited aerobic glycolysis, accompanied by reduced expression of glycolytic enzymes. However, the changes caused by NPAS2 knockdown were partly restored by ARRB1 overexpression. In conclusion, our study suggests that ARRB1 could transcriptionally activate NPAS2, facilitating malignant activities and glycolysis, and ultimately promoting the progression of LUAD, proving a novel therapeutic strategy for the treatment of LUAD.

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Identification of circadian clock genes as regulators of immune infiltration in Hepatocellular Carcinoma

Cited by 11 publications

References 46 publications

Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma

Characterization of molecular subtypes based on chromatin regulators and identification of the role of NPAS2 in lung adenocarcinoma

NPAS2, A Circadian Hemeprotein and Gas-Responsive Transcription Factor

NPAS2, transcriptionally activated by ARRB1, promotes the malignant behaviours of lung adenocarcinoma cells and regulates the reprogramming of glucose metabolism

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