The <b>E3</b> ubiquitin ligase <b>HUWE1</b> is required for <b>KRAS</b>-induced lung cancer

The <b>E3</b> ubiquitin ligase <b>HUWE1</b> modifies a diverse network of substrate proteins by ubiquitination, through which it regulates various intracellular processes and<br/>contributes to both oncogenic and tumour suppressor mechanisms in different<br/>cancer contexts. Here, by analysing human lung adenocarcinoma (<b>LUAD</b>) patient samples we reveal that <b>HUWE1</b> protein expression is commonly upregulated in <b>LUAD</b> tumours compared to normal adjacent lung tissue and that this increase is associated with tumour stage. Using multiple, independent murine models of <b>LUAD</b> initiation and growth, we identify that <i><b>Huwe1</b> </i>is essential for mutant<i> <b>Kras</b></i>-induced lung tumour development and reveal a novel, p53-independent requirement for <i><b>Huwe1</b></i> in <b>LUAD</b>. Mechanistically, we demonstrate induction of senescence following <b>HUWE1</b> 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 (<b>SASP</b>) signalling and <b>NFκB </b>activation. Together, these data highlight a crucial role for <b>HUWE1</b> in mutant <i><b>Kras</b></i>-induced <b>LUAD</b> tumorigenesis and in the continued growth and proliferation of established <b>LUAD </b>cells, confirming <b>HUWE1</b> as a rational therapeutic target for <b>LUAD</b>.<br/>