MITF Targets in Gastrointestinal Stromal Tumors: Implication in Autophagy and Extracellular Vesicle Secretion

Abstract

Previous studies have identified Microphthalmia-associated Transcription Factor (MITF) involvement in regulating Gastrointestinal Stromal Tumors (GIST) growth and cell cycle progression. This study uses Chromatin Immunoprecipitation combined with high-throughput sequencing (ChIP-seq) and RNA sequencing to explore MITF-modulated genes in GIST. Our findings reveal that MITF regulates genes involved in lysosome biogenesis, vesicle generation, autophagy, and mTOR signaling pathways. Comparative transcriptome analysis following MITF silencing in GIST cells shows differential enrichment in mTOR signaling, impacting tumor growth and autophagy. In the context of cancer, the interplay between autophagy and extracellular vesicle release can influence tumor progression and metastasis. We examined MITF's role in autophagy and extracellular vesicle (EV) production in GIST, finding that MITF overexpression increases autophagy, as shown by elevated LC3II levels while silencing MITF disrupts autophagosome and autolysosome formation. Despite no significant changes in EV size or number, MITF silencing notably reduces KIT expression in EV content. KIT secretion in EVs has been linked to GIST metastasis, suggesting that MITF is a crucial target for managing tumor growth and metastasis in GIST.