Melatonin modulates metabolic remodeling in HNSCC by suppressing MTHFD1L‐formate axis

Cui, Li; Zhao, Xinyuan; Jin, Zhenning; Wang, Hailin; Yang, Shun‐Fa; Hu, Shen

doi:10.1111/jpi.12767

Cited by 17 publications

(10 citation statements)

References 49 publications

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“…The PTEN shRNA lentiviral particles were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA, USA). Lentiviruses with circBIRC6 overexpression/inhibition and PTEN overexpression were produced as previously described [ 16 ]. The PDLSCs were infected with lentiviruses and/or transfected with miRNA mimics/inhibitors using Lipofectamine 3000 (Invitrogen, Carlsbad, CA, USA) according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Circular RNA BIRC6 depletion promotes osteogenic differentiation of periodontal ligament stem cells via the miR-543/PTEN/PI3K/AKT/mTOR signaling pathway in the inflammatory microenvironment

et al. 2022

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Background Periodontal ligament stem cells (PDLSCs) are the ideal seed cells for periodontal tissue regeneration. It is well established that persistent inflammation significantly impairs the osteogenic differentiation capability of PDLSCs. Therefore, maintaining PDLSC osteogenic potential under the inflammatory microenvironment is important for treating bone loss in periodontitis. The aim of our study was to explore the potential role of circular RNA BIRC6 (circBIRC6) in regulating osteogenic differentiation of PDLSCs in the inflammatory conditions. Methods Alkaline phosphatase staining, Alizarin Red staining, quantitative real-time polymerase chain reaction, western blotting and immunofluorescence staining were used to evaluated the effects of circBIRC6 on the osteogenic differentiation of PDLSCs. RNA pull-down and luciferase assays were performed to explore the interaction between circBIRC6 and miR-543. Then, the downstream signaling pathway affected by circBIRC6/miR-543 axis was further investigated. Results The expression level of circBIRC6 was higher in PDLSCs exposed to inflammatory stimulus and in periodontitis tissues compared to the respective controls. Downregulation of circBIRC6 enhanced the osteogenic potential of PDLSCs under the inflammatory conditions, and upregulation of circBIRC6 led to opposite findings. Mechanistically, we found that circBIRC6 modulated PDLSC osteogenic differentiation through sponging miR-543. More importantly, we have demonstrated that circBIRC6/miR-543 axis regulated the mineralization capacity of PDLSCs via PTEN/PI3K/AKT/mTOR signaling pathway in the inflammatory microenvironment. Conclusions In summary, the expression of miR-543 is significantly increased following circBIRC6 downregulation, leading to inhibition of PTEN and subsequently activation of PI3K/AKT/mTOR signaling pathway. Therefore, targeting circBIRC6 might represent a potential therapeutic strategy for improving bone loss in periodontitis.

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Section: Methodsmentioning

confidence: 99%

Circular RNA BIRC6 depletion promotes osteogenic differentiation of periodontal ligament stem cells via the miR-543/PTEN/PI3K/AKT/mTOR signaling pathway in the inflammatory microenvironment

et al. 2022

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“…The ChIP assays were performed with a ChIP assay kit (Millipore, Billerica, MA, USA) as previously described. 40 The cells were cross-linked with 1% formaldehyde for 10 min at room temperature to cross-link proteins to DNA, and the reaction was terminated by adding 125 mmol·L −1 glycine. After washing twice with cold PBS, the cells were lysed in RIPA buffer and sonicated to generate DNA fragments.…”

Section: Methodsmentioning

confidence: 99%

FAM64A promotes HNSCC tumorigenesis by mediating transcriptional autoregulation of FOXM1

et al. 2022

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Head and neck squamous cell carcinoma (HNSCC) still lacks effective targeted treatment. Therefore, exploring novel and robust molecular targets is critical for improving the clinical outcome of HNSCC. Here, we reported that the expression levels of family with sequence similarity 64, member A (FAM64A) were significantly higher in HNSCC tissues and cell lines. In addition, FAM64A overexpression was found to be strongly associated with an unfavorable prognosis of HNSCC. Both in vitro and in vivo evidence showed that FAM64A depletion suppressed the malignant activities of HNSCC cells, and vice versa. Moreover, we found that the FAM64A level was progressively increased from normal to dysplastic to cancerous tissues in a carcinogenic 4-nitroquinoline-1-oxide mouse model. Mechanistically, a physical interaction was found between FAM64A and forkhead box protein M1 (FOXM1) in HNSCC cells. FAM64A promoted HNSCC tumorigenesis not only by enhancing the transcriptional activity of FOXM1, but also, more importantly, by modulating FOXM1 expression via the autoregulation loop. Furthermore, a positive correlation between FAM64A and FOXM1 was found in multiple independent cohorts. Taken together, our findings reveal a previously unknown mechanism behind the activation of FOXM1 in HNSCC, and FAM64A might be a promising molecular therapeutic target for treating HNSCC.

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“…Head and neck cancer (HNC) is the sixth most common cancer globally, and squamous cell carcinoma (HNSCC) is the most prevalent histological subtype, constituting up to 90% of all HNC cases [ 1 ]. HNSCC is derived from the mucosal epithelium lining the oral cavity, pharynx and larynx [ 2 , 3 ]. Although it is well established that HNSCC develops from different degrees of neoplasia to eventually become invasive carcinoma, most HNSCC cases are diagnosed at late phases when aggressive treatments are needed.…”

Section: Introductionmentioning

confidence: 99%

PLEK2 promotes cancer stemness and tumorigenesis of head and neck squamous cell carcinoma via the c‐Myc‐mediated positive feedback loop

Zhao

Shu

Sun

et al. 2022

Cancer Communications

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Background Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent malignancies worldwide and is characterized by unfavorable prognosis, high lymph node metastasis and early recurrence. However, the molecular events regulating HNSCC tumorigenesis remain poorly understood. Therefore, uncovering the underlying mechanisms is urgently needed to identify novel and promising therapeutic targets for HNSCC. In this study, we aimed to explore the role of pleckstrin‐2 (PLEK2) in regulating HNSCC tumorigenesis. Methods The expression pattern of PLEK2 and its clinical significance in HNSCC were determined by analyzing publicly assessable datasets and our own independent HNSCC cohort. In vitro and in vivo experiments, including cell proliferation, colony formation, Matrigel invasion, tumor sphere formation, ALDEFLUOR, Western blotting assays and xenograft mouse models, were used to investigate the role of PLEK2 in regulating the malignant behaviors of HNSCC cells. The underlying molecular mechanisms for the tumor‐promoting role of PLEK2 were elucidated using co‐immunoprecipitation, cycloheximide chase analysis, ubiquitination assays, chromatin immunoprecipitation‐quantitative polymerase chain reaction, luciferase reporter assays and rescue experiments. Results The expression levels of PLEK2 mRNA and protein were significantly increased in HNSCC tissues, and PLEK2 overexpression was strongly associated with poor overall survival and therapeutic resistance. Additionally, PLEK2 was important for maintaining the proliferation, invasion, epithelial‐mesenchymal transition, cancer stemness and tumorigenesis of HNSCC cells and could alter the cellular metabolism of the cancer cells. Mechanistically, PLEK2 interacted with c‐Myc and reduced the association of F‐box and WD repeat domain containing 7 (FBXW7) with c‐Myc, thereby avoiding ubiquitination and subsequent proteasome‐mediated degradation of c‐Myc. Moreover, the c‐Myc signaling activated by PLEK2 was important for sustaining the aggressive malignant phenotypes and tumorigenesis of HNSCC cells. c‐Myc also directly bounded to the PLEK2 promoter and activated its transcription, forming a positive feedback loop. Conclusions Collectively, these findings uncover a previously unknown molecular basis of PLEK2‐enhanced c‐Myc signaling in HNSCC, suggesting that PLEK2 may represent a promising therapeutic target for treating HNSCC.

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Melatonin modulates metabolic remodeling in HNSCC by suppressing MTHFD1L‐formate axis

Cited by 17 publications

References 49 publications

Circular RNA BIRC6 depletion promotes osteogenic differentiation of periodontal ligament stem cells via the miR-543/PTEN/PI3K/AKT/mTOR signaling pathway in the inflammatory microenvironment

Circular RNA BIRC6 depletion promotes osteogenic differentiation of periodontal ligament stem cells via the miR-543/PTEN/PI3K/AKT/mTOR signaling pathway in the inflammatory microenvironment

FAM64A promotes HNSCC tumorigenesis by mediating transcriptional autoregulation of FOXM1

PLEK2 promotes cancer stemness and tumorigenesis of head and neck squamous cell carcinoma via the c‐Myc‐mediated positive feedback loop

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