scholarly journals BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous cell carcinoma

2017 ◽  
Author(s):  
Kyren A. Lazarus ◽  
Fazal Hadi ◽  
Elisabetta Zambon ◽  
Karsten Bach ◽  
Maria-Francesca Santolla ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cancer Genomics ◽  
Lung Squamous Cell Carcinoma ◽  
Basal Cells ◽  
Reserve Cell ◽  
Targeted Therapeutic

AbstractPatients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted therapeutic options. We report here the identification and characterisation of the transcriptional regulator,BCL11A, as a LUSC oncogene. Analysis of cancer genomics datasets revealedBCL11Ato be upregulated in LUSC but not lung adenocarcinoma (LUAD). We demonstrated that knockdown ofBCL11Ain LUSC cell lines abolished xenograft tumour growth and its overexpressionin vivoled to lung airway hyperplasia and the development of reserve cell hyperplastic lesions. In addition, deletion ofBcl11ain the tracheal basal cells abolished the development of tracheosphere organoids while its overexpression led to solid tracheospheres with a squamous phenotype. At the molecular level we foundBCL11Ato be a target of SOX2 and we show that it is required for the oncogenic role of SOX2 in LUSC. Furthermore, we showed thatBCL11Aand SOX2 interact at the protein level and that together they co-regulated the expression of several transcription factors. We demonstrate that pharmacological inhibition of SETD8, a gene co-regulated by BCL11A and SOX2, alone or in combination with cisplatin treatment, shows significant selectivity to LUSC in comparison to LUAD cells. Collectively, these results indicate that the disruption of the BCL11A-SOX2 transcriptional program provides a future framework for the development of targeted therapeutic intervention for LUSC patients.

scholarly journals Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/HIF-1α signal axis

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiaofeng Qi ◽  
Wengguang Xu ◽  
Junqi Xie ◽  
Yufeng Wang ◽  
Shengwei Han ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Carcinoma Cells ◽  
Oral Cancers ◽  
Underlying Mechanisms

Abstract Resistance towards chemotherapy is a common complication in treatment of oral cancers, which leads to treatment failure and poor outcome. In recent years, a growing body of evidence has shown that tumour hypoxia significantly contributes to chemoresistance. Metformin, a widely used oral hypoglycaemic drug, can reportedly potentiate the efficacy of chemotherapeutic drugs in various cancers; however, the underlying mechanisms are intricate and have not been fully understood. In this study, we explored the role of metformin in chemosensitivity of oral squamous cell carcinoma cells (OSCC) to cisplatin both in vitro and in vivo, and attempted to elucidate its possible underlying mechanisms. Encouragingly, we found that metformin synergistically enhanced cisplatin cytotoxicity and reversed the chemoresistance to certain extent. This mechanism could likely be related with inhibition of the NF-κB/HIF-1α signal axis and lead to the downregulation of hypoxia-regulated genes products. Therefore, metformin could serve as a chemosensitiser for cisplatin-based regimens for OSCC, thereby providing a theoretical basis for future use in the treatment of oral cancers.

scholarly journals NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma

2017 ◽  
Author(s):  
Kevin Brennan ◽  
June Ho Shin ◽  
Joshua K. Tay ◽  
Marcos Prunello ◽  
Andrew Gentles ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lung Squamous Cell Carcinoma ◽  
Intrinsic Subtype ◽  
Sotos Syndrome ◽  
Dna Hypomethylation ◽  
General Role ◽  
Inactivating Mutations

AbstractChromatin modifying enzymes are frequently mutated in cancer, resulting in a cascade of epigenetic deregulation. Recent reports indicate that inactivating mutations in the histone methyltransferase NSD1 define an intrinsic subtype of head and neck squamous cell carcinoma (HNSC) that features widespread DNA hypomethylation. Here, we describe a similar DNA hypomethylated subtype of lung squamous cell carcinoma (LUSC) that is enriched for both inactivating mutations and deletions inNSD1. The ‘NSD1 subtype’ of HNSC and LUSC are highly correlated at the DNA methylation and gene expression levels, with concordant DNA hypomethylation and overexpression of a strongly overlapping set of genes, a subset of which are also hypomethylated in Sotos syndrome, a congenital growth disorder caused by germlineNSD1mutations. Further, the NSD1 subtype of HNSC displays an ‘immune cold’ phenotype characterized by low infiltration of tumor-associated leukocytes, particularly macrophages and CD8+T cells, as well as low expression of genes encoding the immunotherapy target PD-1 immune checkpoint receptor and its ligands PD-L1 and PD-L2. Using anin vivomodel, we demonstrate that NSD1 inactivation results in a reduction in the degree of T cell infiltration into the tumor microenvironment, implicating NSD1 as a tumor cell-intrinsic driver of an immune cold phenotype. These data have important implications for immunotherapy and reveal a general role of NSD1 in maintaining epigenetic repression.

scholarly journals Hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT axis

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Peng Xu ◽  
Kang Hu ◽  
Ping Zhang ◽  
Zhi-Gang Sun ◽  
Nan Zhang
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lung Squamous Cell Carcinoma ◽  
Akt Signaling ◽  
In Vitro Assays ◽  
Domain Family ◽  
Yth Domain

Abstract Background N6-methyladenosine (m6A) is a dynamic and reversible internal RNA structure of eukaryotic mRNA. YTH domain family 2 (YTHDF2), an m6A-specific reader YTH domain family, plays fundamental roles in several types of cancer. However, the function of YTHDF2 in lung squamous cell carcinoma (LUSC) remains elusive. Methods The knockdown and overexpression of YTHDF2 in LUSC cells were conducted to detect the biological characteristics of YTHDF2. In vivo assays, the role of YTHDF2 in tumor growth was further uncovered. In vitro assays, YTHDF2 was confirmed to be involved in activating the mTOR/AKT signaling and YTHDF2 overexpression induced the EMT process in LUSC. Clinically, immunohistochemical staining revealed the relationship between YTHDF2 expression levels and the clinicopathological characteristics of lung squamous cell carcinoma patients. Moreover, quantitative PCR (qPCR), western blot, CCK8 assay, transwell assay, and wound-healing assay were used to detect the expression level and function of YTHDF2 under hypoxia exposure in LUSC cells. Results The results showed that hypoxia-mediated YTHDF2 overexpression promotes cell proliferation and invasion by activating the mTOR/AKT axis, and YTHDF2 overexpression induces the EMT process in LUSC. Moreover, YTHDF2 is closely associated with pN (pN– 37.0%, pN + 73.9%; P = 0.002) and pTNM stage (pI 50.0%, PII 43.3%, pIIIa 80.6%; P = 0.007), ultimately resulting in poor survival for LUSC patients. Conclusion In brief, the results highlight high-YTHDF2 expression predicted a worse prognosis of LUSC, while hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT signaling pathway.

The role of protein tyrosine phosphatase non-receptor 11 (PTPN11) mutations in lung squamous cell carcinoma (SQCC).

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. e22174-e22174
Author(s):  
Yasir Elamin ◽  
Sinead Toomey ◽  
Aoife Carr ◽  
Kenneth O'Byrne ◽  
Shereen Rafee ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Lung Squamous Cell Carcinoma ◽  
Protein Tyrosine

Abstract 2308: The role of LKB1 in development of lung squamous cell carcinoma in mice

2015 ◽  
Author(s):  
Jian Liu ◽  
Sung-Nam Cho ◽  
Yiqun Zhang ◽  
Chad J. Creighton ◽  
Francesco J. DeMayo
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lung Squamous Cell Carcinoma

scholarly journals Prognostic Role of the FGFR4-388Arg Variant in Lung Squamous-Cell Carcinoma Patients With Lymph Node Involvement

2017 ◽  
Vol 18 (6) ◽  
pp. 667-674.e1 ◽  
Author(s):  
Álvaro Quintanal-Villalonga ◽  
Andrés Carranza-Carranza ◽  
Ricardo Meléndez ◽  
Irene Ferrer ◽  
Sonia Molina-Pinelo ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Lymph Node ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Lung Squamous Cell Carcinoma ◽  
Lymph Node Involvement ◽  
Prognostic Role ◽  
Node Involvement
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