Upregulation of amplified in breast cancer 1 contributes to pancreatic ductal adenocarcinoma progression and vulnerability to blockage of hedgehog activation

• Published in: Theranostics 2021, Vol.11 (4), p.1672-1689
• Main Authors: Li, Licen, Bao, Jiaolin, Wang, Haitao, Lei, Josh Haipeng, Peng, Cheng, Zeng, Jianming, Hao, Wenhui, Zhang, Xu, Xu, Xiaoling, Yu, Chundong, Deng, Chu-Xia, Chen, Qiang
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast cancer; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - secondary; Cell adhesion & migration; Cell cycle; Cell growth; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Humans; Ligands; Male; Medical prognosis; Metastasis; Mice; Mice, SCID; Nuclear Receptor Coactivator 3 - genetics; Nuclear Receptor Coactivator 3 - metabolism; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Plasmids; Prognosis; Research Paper; Survival Rate; Transcription factors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.47390

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and devastating cancers without effective treatments. Amplified in breast cancer 1 (AIB1) is a member of the steroid receptor coactivator family that mediates the transcriptional activities of nuclear receptors. While AIB1 is associated with the initiation and progression of multiple cancers, the mechanism by which AIB1 contributes to PDAC progression remains unknown. In this study, we aimed to explore the role of AIB1 in the progression of PDAC and elucidate the underlying mechanisms. The clinical significance and mRNA level of AIB1 in PDAC were studied by database analysis. To demonstrate whether AIB1 mediates the malignant features of PDAC cells, namely, proliferation, migration, invasion, we performed real-time PCR and Western blot analysis, established xenograft models and used metastasis assay. With insights into the mechanism of AIB1, we performed RNA sequencing (Seq), ChIP-Seq, luciferase reporter assays and pull-down assays. Furthermore, we analyzed the relationship between AIB1 expression and its target expression in PDAC cells and patients and explored whether PDAC cells with high AIB1 levels are sensitive to inhibitors of its target. We found that AIB1 was significantly upregulated in PDAC and associated with its malignancy. Silencing AIB1 impaired hedgehog (Hh) activation by reducing the expression of smoothened (SMO), leading to cell cycle arrest and the inhibition of PDAC cell proliferation. In addition, AIB1, upregulation of integrin αv (ITGAV) expression, promoted extracellular matrix (ECM) signaling, which played an important role in PDAC progression. Further studies showed that AIB1 preferably bound to AP-1 related elements and served as a coactivator for enhancing the transcriptional activity of MafB, which promoted the expression of SMO and ITGAV. PDAC cells with high AIB1 levels were sensitive to Hh signaling inhibitors, suggesting that blocking Hh activation is an effective treatment against PDAC with high AIB1 expression. These findings reveal that AIB1 is a crucial oncogenic regulator associated with PDAC progression Hh and ECM signaling and suggest potential therapeutic targets for PDAC treatment.