STIL Acts as an Oncogenetic Driver in a Primary Cilia-Dependent Manner in Human Cancer

Abstract

SCL/TAL1 Interrupting locus (STIL) is a ciliary-related gene involved in regulating the cell cycle and duplication of centrioles in dividing cells. STIL has been found disordered in multiple cancers and driven carcinogenesis. However, the molecular mechanisms and biological functions of STIL in cancers remain ambiguous. Here, we systematically analyzed the genetic alterations, molecular mechanisms, and clinical relevance of STIL across >10,000 samples representing 33 cancer types in The Cancer Genome Atlas (TCGA) dataset. We found that STIL expression is up-regulated in most cancer types compared with their adjacent normal tissues. The expression dysregulation of STIL was affected by copy number variation, mutation, and DNA methylation. High STIL expression was associated with worse outcomes and promoted the progression of cancers. Gene Ontology (GO) enrichment analysis and Gene Set Variation Analysis (GSVA) further revealed that STIL is involved in cell cycle progression, Mitotic spindle, G2M checkpoint, and E2F targets pathways across cancer types. STIL expression was negatively correlated with multiple genes taking part in ciliogenesis and was positively correlated with several genes which participated with centrosomal duplication or cilia degradation. Moreover, STIL silencing could promote primary cilia formation and inhibit cell cycle protein expression in prostate and kidney cancer cell lines. The phenotype and protein expression alteration due to STIL silencing could be reversed by IFT88 silencing in cancer cells. These results revealed that STIL could regulate the cell cycle through primary cilia in tumor cells. In summary, our results revealed the importance of STIL in cancers. Targeting STIL might be a novel therapeutic approach for cancers.

STIL/AURKA axis promotes cell proliferation by influencing primary cilia formation in bladder cancer

“…S2A–D). A previous study has shown that PC is closely related to the cell cycle [ 16 , 21 ]. IFT88 also has been demonstrated to play a crucial role in regulating the cell cycle [ 22 , 23 ].…”

“…1 F), we called them prognosis-related PC genes (PRPGs). We first focus on STIL, which has been found to influence cell cycle progression by regulating the PC in kidney and prostate cancer in our previous study [ 16 ]. In the TCGA-BLCA dataset, STIL mRNA expression was up-regulated in tumour tissue, and the patients with high STIL expression showed a worse prognosis (Fig.…”

“…S3E–I). STIL is a centriole protein involved in regulating the cell cycle and duplication of centrioles in dividing cells [ 16 , 26 ], so we further detected the effect of STIL in the cell cycle of BLCA cells. The cell cycle analysis showed that the percentage of cells in the quiescent phase (G0/G1) was higher in STIL-depleted cells and lower in STIL-overexpressed cells compared to normal control, suggesting that STIL is involved in cell cycle G1 to S phase transition in BLCA cells (Fig.…”

“…In our previous study, STIL is up-regulated in tumor tissues and is closely related to the bad prognosis of patients. STIL could regulate PC and affect the cell cycle of kidney and prostate cancer cells [ 16 ]. This study found that STIL expression was up-regulated in bladder cancer tissues and cell lines.…”

Role of estrogen receptor signaling pathway-related genes in diffuse large B-cell lymphoma and identification of key targets via integrated bioinformatics analysis and experimental validation

“…In liver cancer, low expression of KIF20A inhibits cell proliferation, promotes chemosensitivity, and is associated with a better prognosis ( 53 ). STIL acts as an oncogene driver in a primary cilia-dependent manner in human cancer ( 54 ). STIL is integral in regulating cancer cell motility through plate oval accumulation of the ARHGEF7-PAK1 complex ( 55 ).…”