KIF11 manipulates SREBP2‐dependent mevalonate cross talk to promote tumor progression in pancreatic ductal adenocarcinoma. (26th May 2022)

• Record Type: Journal Article
• Authors: Gu, Xiang; Zhu, Qunshan; Tian, Guangyu; Song, Wenbo; Wang, Tao; Wang, Ali; Chen, Xiaojun; Qin, Songbing
• Is Part Of: Cancer medicine. Volume 11:Number 17(2022)
• Page Start: 3282
• Page End: 3295
• Publication Date: 2022-05-26
• Subjects: KIF11 -- mevalonate metabolism -- PDAC -- SREBP2 -- ubiquitination; 616.994005
• DOI: 10.1002/cam4.4683
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: Cholesterol metabolism is highly correlated with risks of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, the underlying mechanisms of activation of cholesterol biogenesis remain inconclusive. KIF11 is a key component of the bipolar spindle and expresses highly in various malignancies. However, its functional role in PDAC tumorigenesis is still unclear. This study aims to elucidate the oncogenic functions of KIF11 in stimulating cholesterol metabolism, thereby driving PDAC progression. We utilized bioinformatics analysis to identify that KIF11 expressed highly in tumor samples versus paired normal tissues and high KIF11 correlated with high clinical stages of patients. Patients with high KIF11 had worse survival outcomes relative to those with low KIF11. Gene set enrichment analysis (GSEA) revealed that KIF11 correlated intensively with the mevalonate (MVA) metabolic pathway. Positive associations were observed between KIF11 and MVA‐signature (HMGCR, FDFT1, SQLE, and MSMO1). KIF11 could elevate the free cholesterol content of PDAC cells and targeting MVA inhibited the in vitro growth of KIF11‐overexpressing cells. Mechanistically, we found KIF11 could interact with SREBP2, the master regulator of MVA. High KIF11 could increase SREBP2 proteins, but not alter their mRNA levels. KIF11 could attenuate the ubiquitination‐mediated degradation of SREBP2, thereby enhancing its stability and accumulation. Accordingly, KIF11 stimulated the expressions of MVA‐signature and free cholesterol contents depending on SREBP2. In addition, KIF11 depended on SREBP2 to promote cell growth, migration, stemness, and colony formation abilities. The subcutaneous xenograft models indicated that targeting MVA biogenesis (atorvastatin) is effective to restrict the in vivo growth of KIF11 high PDAC. Taken together, our study identified that KIF11 could activate the MVA cross talk to drive PDAC progression and inhibiting the KIF11/MVA axis provided a therapeutic vulnerability in the treatment of PDAC. Abstract : Our study identified that KIF11 could activate the MVA crosstalk to drive PDAC progression and inhibiting KIF11/MVA axis provided a therapeutic vulnerability in the treatment of PDAC.