YAP-dependent bip induction is involved in nicotine- mediated oral cancer Malignancy

Chu Yen Chien, Ying Chen Chen, Chia Chen Hsu, Yu Ting Chou, Shine Gwo Shiah, Shyun Yeu Liu, Alexander Cheng Ting Hsieh, Ching Yu Yen, Chien Hsing Lee, Yi Shing Shieh

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Cigarette smoking is a significant risk factor for the development and progression of oral cancer. Previous studies have reported an association between nicotine and malignancy in oral can-cer. Recent studies have also demonstrated that nicotine can induce endoplasmic reticulum (ER) stress in tumor cells. Binding immunoglobulin protein (BiP) acts as a master regulator of ER stress and is frequently overexpressed in oral cancer cell lines and tissues. However, the effect of nicotine on BiP in oral cancer is unknown. Therefore, this study aimed to evaluate the role of BiP and its underlying regulatory mechanisms in nicotine-induced oral cancer progression. Our results showed that nicotine significantly induced the expression of BiP in time- and dose-dependent man-ners in oral squamous cell carcinoma (OSCC) cells. In addition, BiP was involved in nicotine-medi-ated OSCC malignancy, and depletion of BiP expression remarkably suppressed nicotine-induced malignant behaviors, including epithelial–mesenchymal transition (EMT) change, migration, and invasion. In vivo, BiP silencing abrogated nicotine-induced tumor growth and EMT switch in nude mice. Moreover, nicotine stimulated BiP expression through the activation of the YAP-TEAD transcriptional complex. Mechanistically, we observed that nicotine regulated YAP nuclear transloca-tion and its interaction with TEAD through α7-nAChR-Akt signaling, subsequently resulting in increased TEAD occupancy on the HSPA5 promoter and elevated promoter activity. These observa-tions suggest that BiP is involved in nicotine-induced oral cancer malignancy and may have therapeutic potential in tobacco-related oral cancer.

Original languageEnglish
Article number2080
JournalCells
Volume10
Issue number8
DOIs
Publication statusPublished - Aug 2021

Keywords

  • Chaperons
  • Cigarette smoking
  • Nicotinic acetylcholine receptors
  • Oncogenes
  • Oral squa-mous cell carcinoma

ASJC Scopus subject areas

  • Medicine(all)

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