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Next Generation Sequencing Facilitates Quantitative Analysis of healthy indiviual and HUWE1-promoted XLID Transcriptomes

ABSTRACT: mRNA profiles of healthy vs HUWE1 mutant cells were generated by deep sequencing, in triplicate, using Illumina HiSeq 4000 (single read, 75bp).

ORGANISM(S): Homo sapiens

PROVIDER: GSE130551 | GEO | 2021/03/06

REPOSITORIES: GEO

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Next Generation Sequencing Facilitates Quantitative Analysis of healthy indiviual and HUWE1-promoted XLID Transcriptomes

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The E3 ubiquitin ligase HUWE1 is required for KRAS-induced lung cancer

Project description:The E3 ubiquitin ligase HUWE1 modifies a diverse network of substrate proteins by ubiquitination, through which it regulates various intracellular processes and contributes to both oncogenic and tumour suppressor mechanisms in different cancer contexts. Here, by analysing human lung adenocarcinoma (LUAD) patient samples, we reveal that HUWE1 protein expression is commonly upregulated in LUAD tumours compared to normal adjacent lung tissue and that this increase is associated with tumour stage. Using multiple, independent murine models of LUAD initiation and growth, we identify that Huwe1 is essential for mutant Kras-induced lung tumour development and reveal a novel, p53-independent requirement for Huwe1 in LUAD. Mechanistically, we demonstrate induction of senescence following HUWE1 depletion - characterised by impaired proliferation, an atypical cell cycle distribution, emergence of morphologically abnormal enlarged cells, increased β-galactosidase activity, and transcriptional reprogramming associated with inflammatory senescence-associated secretory phenotype (SASP) signalling and NFκB activation. Together, these data highlight a crucial role for HUWE1 in mutant Kras-induced LUAD tumorigenesis and in the continued growth and proliferation of established LUAD cells, confirming HUWE1 as a rational therapeutic target for LUAD.

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Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

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The ubiquitin ligase HUWE1 regulates hematopoietic stem cell maintenance and lymphoid commitment [microarray]

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