EGF/EGFR‐YAP1/TEAD2 signaling upregulates STIM1 in vemurafenib resistant melanoma cells

• Published in: The FEBS journal Vol. 291; no. 22; pp. 4969 - 4983
• Main Authors: Bai, Weiyu, Yan, Chenghao, Yang, Yichen, Sang, Lei, Hao, Qinggang, Yao, Xinyi, Zhang, Yingru, Yu, Jia, Wang, Yifan, Li, Xiaowen, Meng, Mingyao, Yang, Jilong, Shen, Junling, Sun, Yan, Sun, Jianwei
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.11.2024
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; AKT protein; Animals; BRAF inhibition; calcium; Calcium (reticular); Calcium ions; Carcinogenesis; Carcinogens; Cell Line, Tumor; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; domain; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; EGF/EGFR; Endoplasmic reticulum; Epidermal growth factor; Epidermal Growth Factor - metabolism; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Growth factors; Humans; Kinases; Localization; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; neoplasm progression; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Proteins; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Raf protein; Resistance factors; Signal transduction; Signal Transduction - drug effects; STIM1; STIM1 protein; Stromal Interaction Molecule 1 - genetics; Stromal Interaction Molecule 1 - metabolism; TEA Domain Transcription Factors - metabolism; therapeutics; transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Up-regulation; Up-Regulation - drug effects; Vemurafenib - pharmacology; YAP-Signaling Proteins - genetics; YAP-Signaling Proteins - metabolism; YAP1; Yes-associated protein; YAP1; melanoma; STIM1; EGF/EGFR; BRAF inhibition
• DOI: 10.1111/febs.17272
• ISSN: 1742-464X; 1742-4658

Stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum Ca2+ sensor for store‐operated calcium entry and is closely associated with carcinogenesis and tumor progression. Previously, we found that STIM1 is upregulated in melanoma cells resistant to the serine/threonine‐protein kinase B‐raf inhibitor vemurafenib, although the mechanism underlying this upregulation is unknown. Here, we show that vemurafenib resistance upregulates STIM1 through an epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR)‐Yes‐associated protein 1 (YAP1)/TEA domain transcription factor 2 (TEAD2) signaling axis. Vemurafenib resistance can lead to an increase in EGF and EGFR levels, causing activation of the EGFR signaling pathway, which promotes YAP1 nuclear localization to increase the expression of STIM1. Our findings not only reveal the mechanism by which vemurafenib resistance promotes STIM1 upregulation, but also provide a rationale for combined targeting of the EGF/EGFR‐YAP1/TEAD2‐STIM1 axis to improve the therapeutic efficacy of BRAF inhibitor in melanoma patients. We show that vemurafenib resistance leads to increased transcription of epidermal growth factor (EGF) and activation of EGF/epidermal growth factor receptor (EGFR) signaling in melanoma cells, which promotes Yes‐associated protein 1 (YAP1) nuclear localization, consequently resulting in the transcription of stromal interaction molecule 1 (STIM1).