The roles of m6A RNA methylation modification in cancer stem cells: new opportunities for cancer suppression

Recent studies have shown that abnormal expression of the core circadian clock gene, retinoic acid‐related orphan receptor β (RORβ), is closely associated with the occurrence and progression of various malignant tumors. However, the expression and function of RORβ in head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we comprehensively investigated the altered expression, clinical significance, prognostic value, and biological functions of RORβ in HNSC, as well as its correlation with changes in the tumor immune microenvironment. We found that RORβ expression was decreased in HNSC and 19 other cancers. Low RORβ expression was significantly associated with tumor size, clinical stage, and survival time in HNSC patients, indicating that it may have diagnostic and prognostic value in HNSCC. Epigenetic analysis showed that the promoter methylation level of RORβ was significantly higher in HNSCC compared to adjacent noncancerous tissues. Furthermore, RORβ hypermethylation was significantly associated with low expression levels of RORβ and poor prognosis in HNSCC patients (p < 0.05). Enrichment analysis found that RORβ was involved in immune system regulation and T‐cell activation, as well as the PI3K/AKT and ECM receptors interaction pathways. In vitro assays revealed that RORβ regulated the proliferation, migration and invasion ability of HNSCC cells. Additionally, we found that RORβ expression was significantly correlated with changes in the tumor immune microenvironment, suggesting it may affect prognosis by regulating immune infiltration in HNSC patients. Therefore, RORβ may serve as a potential prognostic biomarker and therapeutic target for HNSCC patients.

Section: Methodsmentioning

confidence: 99%

“…The Spearman rank correlation test was used to draw the coexpression heatmap of ROR β and RNA m 6 A-regulated genes with the R package ggplot2. 23,24…”

Section: Rna Methylation Of N 6 Adenosine (M 6 A) Analysismentioning

confidence: 99%

Comprehensive analysis of the prognosis and biological significance of ROR_β in head and neck squamous cell carcinoma

Zheng

Tang

Yang

et al. 2023

“…Cancer stem cells (CSCs) have emerged as a key focus in cancer research due to their involvement in tumor initiation, progression, and therapy resistance. 3,4 CSCs possess self-renewal capabilities and exhibit high tumorigenic potential, contributing to tumor recurrence and metastasis. 5 Identifying the molecular mechanisms that regulate CSCs is of paramount importance for developing effective therapeutic strategies against EC.…”

Section: Introductionmentioning

confidence: 99%

“…10 Additionally, BRD4 has been implicated in the maintenance of CSC populations and the regulation of stemness-associated genes. 4 Given the importance of BRD4 in cancer biology, it is of particular interest to investigate its role in EC and its potential implications for CSC regulation.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional factor BRD4 promotes the stemness of esophageal cancer by activating the nuclear PD‐L1/RelB axis

Li,

Guo,

Guo

et al. 2023

Esophageal cancer (EC) is a prevalent malignancy associated with therapeutic resistance and poor prognosis. This study investigates the role of programmed death‐ligand 1 (PD‐L1) in esophageal cancer stem cell (ECSC) formation. ECSCs were enriched and characterized using various assays. We found that both PD‐L1 and bromodomain‐containing protein 4 (BRD4) were upregulated in ECSCs, promoting their stemness. Inhibiting BRD4 suppressed ECSC markers expression and sphere formation. Furthermore, BRD4 inhibitors downregulated membrane and nuclear PD‐L1 levels, with knockdown of PD‐L1 inhibiting ECSC formation. PD‐L1 degraders also affected PD‐L1 and its downstream effector RelB expression. Moreover, inhibiting RelB influenced sphere formation through interleukin‐6 expression. This study reveals the critical role of the BRD4/nuclear PD‐L1/RelB axis in ECSC formation, highlighting nuclear PD‐L1 as a potential immunotherapeutic target for refractory EC.

“…Then we hypothesized that NIK might regulate HCC stemness, which was never been reported before and tumor stemness is tightly involved in tumor progression. [14][15][16] In the present study, we aimed to reveal the effects and underlying mechanisms of NIK on HCC stemness. Through the in vitro and in vivo experiments, we revealed that NIK positively regulated the CSC-like traits of HCC cells.…”

mentioning

confidence: 99%

NIK‐mediated reactivation of SIX2 enhanced the CSC‐like traits of hepatocellular carcinoma cells through suppressing ubiquitin–proteasome system

Daren

et al. 2023

The critical roles of NF‐κB Inducing Kinase (NIK) in tumor progression have been elucidated in various tumors; however, its effects on hepatocellular carcinoma (HCC) progression are still confusing. Here, we found that NIK level was upregulated in HCC tissues compared to that of normal tissues, and positively correlated with the levels of cancer stem cell (CSC) markers. Then we established HCC cells with NIK‐stable knockdown and found that NIK knockdown suppressed the CSC—like traits of HCC cells through in vivo and in vitro experiments. Mechanistically, we revealed that SIX2 protein level, but not its mRNA level, was significantly reduced in HCC cells with NIK knockdown, which was rescued by MG132 treatment. Furthermore, NIK knockdown promoted the ubiquitination level of SIX2 and decreased its protein stability. Moreover, Six2 overexpression partially reversed the inhibition of NIK knockdown on the CSC‐like traits of HCC cells. This study identified a novel NIK/SIX2 axis conferring HCC stemness.