AFF4 promotes tumorigenesis and tumor-initiation capacity of head and neck squamous cell carcinoma cells by regulating SOX2

Deng, Peng; Wang, Jiongke; Zhang, Xuefeng; Wu, Xingyu; Ji, Ning; Li, Jing; Zhou, Min; Jiang, Lu; Zeng, Xin; Chen, Qianming

doi:10.1093/carcin/bgy046

Cited by 32 publications

(29 citation statements)

References 47 publications

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“…41 In head and neck squamous cell carcinoma cells, AFF4 can improve tumour initiation and tumorigenesis capability though SOX2. 42 Previous research found that Aff4/Af5q31-null mice exhibited azoospermia, suggesting a nonnegligible effect on Sertoli cells. Moreover, in regard to FRAXE, AFF4 remains functionally redundant during brain development.…”

Section: Discussionmentioning

confidence: 99%

AFF4 regulates osteogenic differentiation of human dental follicle cells

Xiao

Zhang

et al. 2020

Int J Oral Sci

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As a member of the AFF (AF4/FMR2) family, AFF4 is a transcription elongation factor that is a component of the super elongation complex. AFF4 serves as a scaffolding protein that connects transcription factors and promotes gene transcription through elongation and chromatin remodelling. Here, we investigated the effect of AFF4 on human dental follicle cells (DFCs) in osteogenic differentiation. In this study, we found that small interfering RNA-mediated depletion of AFF4 resulted in decreased alkaline phosphatase (ALP) activity and impaired mineralization. In addition, the expression of osteogenic-related genes (DLX5, SP7, RUNX2 and BGLAP) was significantly downregulated. In contrast, lentivirus-mediated overexpression of AFF4 significantly enhanced the osteogenic potential of human DFCs. Mechanistically, we found that both the mRNA and protein levels of ALKBH1, a critical regulator of epigenetics, changed in accordance with AFF4 expression levels. Overexpression of ALKBH1 in AFF4-depleted DFCs partially rescued the impairment of osteogenic differentiation. Our data indicated that AFF4 promoted the osteogenic differentiation of DFCs by upregulating the transcription of ALKBH1.

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Section: Discussionmentioning

confidence: 99%

AFF4 regulates osteogenic differentiation of human dental follicle cells

Xiao

Zhang

et al. 2020

Int J Oral Sci

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“…Numerous studies have revealed that altered overexpression of SOX2 is associated with cell proliferation, self-renewal, cancer cells plasticity, anti-apoptosis, tumorigenesis, tumor relapse and chemo-radio resistant leading to bad prognosis in TSCC patients [100] , [101] , [102] , [103] . Interestingly, specific silencing of SOX2 in TSCC significantly inhibits self-renewal and invasion capacities, in-vivo tumorigenicity and increases chemo-radio sensitization [104] .…”

Section: Various Molecular Approaches/signaling Pathways For Targetinmentioning

confidence: 99%

HPV+ve/−ve oral-tongue cancer stem cells: A potential target for relapse-free therapy

Gupta

Kumar

Das

2021

Translational Oncology

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Highlights Tongue squamous cell carcinoma (TSCC) is most aggressive and highly prevalent subtype of head and neck cancer. Majority of tobacco users are HPV −ve and have bad prognosis while HPV +ve TSCCs not using tobacco show better prognosis. Tongue cancer stem cells (TCSCs) are resistant to chemo-radio therapy and responsible for cancer relapse. Targeting TCSCs may provide efficient therapeutic strategy for relapse-free survival of TSCC patients.

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“…As an essential component of SEC, AFF4 can bind to DNA directly and regulate the transcription elongation of many genes. MYC and SOX2, well-known pluripotency factors of CSCs, have been reported to be regulated by AFF4 in BCa [11] and HNSCC [30], respectively. To investigate whether MYC and SOX2 are effectors of AFF4 in regulating the self-renewal capability of BCSCs, we performed CHIP assay in 5637 and UM-UC-3 cells and found AFF4 directly bound to MYC and SOX2 promoter regions, which were barely detectable after AFF4 knockdown ( Figure 5(a)).…”

Section: Aff4 Directly Regulates Myc and Sox2 Gene Expression In Bca mentioning

confidence: 99%

“…As a core component of the super elongation complex (SEC), AFF4 is involved in the regulation of transcription elongation of many genes encoding the pluripotency factors [ 28 , 29 ]. For instance, AFF4 could upregulate SOX2 transcription to promote the tumor-initiation capacity of head and neck squamous cell carcinoma (HNSCC) [ 30 ], and MYC is another known target of AFF4 [ 11 , 31 ]. Inspired by these results, we hypothesized that m 6 A plays a role in promoting the stemness of BCa cells by regulating AFF expression.…”

Section: Introductionmentioning

confidence: 99%

The m⁶A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells

Gao

Zheng

et al. 2020

Stem Cells International

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The dynamic N6-methyladenosine (m6A) modification of mRNA plays a role in regulating gene expression and determining cell fate. However, the functions of m6A mRNA modification in bladder cancer stem cells (BCSCs) have not been described. Here, we show that global RNA m6A abundance and the expression of m6A-forming enzyme METTL3 are higher in BCSCs than those in non-CSCs of bladder cancer (BCa) cells. The depletion of the METTL3 inhibited the self-renewal of BCSCs, as evidenced by decreased ALDH activity and sphere-forming ability. Mechanistically, METTL3 regulates the m6A modification and thereby the expression of AF4/FMR2 family member 4 (AFF4), knockdown of which phenocopies the METTL3 ablation and diminishes the tumor-initiating capability of BCSCs in vivo. AFF4 binds to the promoter regions and sustains the transcription of SOX2 and MYC which have critical biological functions in BCSCs. Collectively, our results demonstrate the critical roles of m6A modification in self-renewal and tumorigenicity of BCSCs through a novel signaling axis of METTL3-AFF4-SOX2/MYC.

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AFF4 promotes tumorigenesis and tumor-initiation capacity of head and neck squamous cell carcinoma cells by regulating SOX2

Abstract: AFF4, an essential core of SEC, was overexpressed in HNSCC tissue and cell lines. AFF4 promoted the proliferation, migration, invasion and tumor-initiation capacity by regulating SOX2 in HNSCC cells, indicating AFF4 may serve as a potential therapeutic target of HNSCC.

Cited by 32 publications

References 47 publications

AFF4 regulates osteogenic differentiation of human dental follicle cells

AFF4 regulates osteogenic differentiation of human dental follicle cells

HPV+ve/−ve oral-tongue cancer stem cells: A potential target for relapse-free therapy

The m⁶A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells

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AFF4 promotes tumorigenesis and tumor-initiation capacity of head and neck squamous cell carcinoma cells by regulating SOX2

Abstract: AFF4, an essential core of SEC, was overexpressed in HNSCC tissue and cell lines. AFF4 promoted the proliferation, migration, invasion and tumor-initiation capacity by regulating SOX2 in HNSCC cells, indicating AFF4 may serve as a potential therapeutic target of HNSCC.

Cited by 32 publications

References 47 publications

AFF4 regulates osteogenic differentiation of human dental follicle cells

AFF4 regulates osteogenic differentiation of human dental follicle cells

HPV+ve/−ve oral-tongue cancer stem cells: A potential target for relapse-free therapy

The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells

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The m⁶A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells