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Cell Death Differ., Sep 13 2023 | https://doi.org/10.1038/s41418-023-01220-2 Identification of novel pathogenic roles of BLZF1/ATF6 in tumorigenesis of gastrointestinal stromal tumor showing Golgi-localized mutant KIT.

Yujin Kwon^1,2,15, Jiyoon Kim^3,15, Su-Yeon Cho^1,2, Yoon Jin Kang^1,4, Jongsoo Lee⁵, Jaeyoung Kwon^2,6, Hyungjin Rhee⁷, Sebastian Bauer⁸, Hyung-Sik Kim⁹, Esak Lee¹⁰, Han Sang Kim¹¹, Jae Hung Jung¹², Hoguen Kim¹³ and Won Kyu Kim^1,14

¹Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, South Korea.

²Division of Bio-Medical Science & Technology, University of Science and Technology (UST), Daejeon 34113, South Korea.

³Department of Pharmacology, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea.

⁴Department of Marine Life Sciences, College of Life Science, Gangneung-Wonju National University, Gangneung 25457, South Korea.

⁵Department of Urology, Urologic Science Institute, Yonsei University College of Medicine, Seoul 03722, South Korea.

⁶Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, South Korea.

⁷Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, South Korea.

⁸Sarcoma Center, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Germany and German Cancer Consortium (DKTK), Essen 45141, Germany.

⁹Department of Oral Biochemistry; Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50612, South Korea.

¹⁰Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.

¹¹Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, South Korea.

¹²Department of Urology, Yonsei University Wonju College of Medicine/Center of Evidence Based Medicine Institute of Convergence Science, Wonju 26426, South Korea. 13Department of Pathology, Yonsei University College of Medicine, Seoul 03722, South Korea.

¹⁴Department of Convergence Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, South Korea.

¹⁵These authors contributed equally: Yujin Kwon, Jiyoon Kim.

Corresponding author : Correspondence to Won Kyu Kim.

Abstract

Gastrointestinal stromal tumors (GISTs) frequently show KIT mutations, accompanied by overexpression and aberrant localization of mutant KIT (MT-KIT). As previously established by multiple studies, including ours, we confirmed that MT-KIT initiates downstream signaling in the Golgi complex. Basic leucine zipper nuclear factor 1 (BLZF1) was identified as a novel MT-KIT-binding partner that tethers MT-KIT to the Golgi complex. Sustained activation of activated transcription factor 6 (ATF6), which belongs to the unfolded protein response (UPR) family, alleviates endoplasmic reticulum (ER) stress by upregulating chaperone expression, including heat shock protein 90 (HSP90), which assists in MT-KIT folding. BLZF1 knockdown and ATF6 inhibition suppressed both imatinib-sensitive and -resistant GIST in vitro. ATF6 inhibitors further showed potent antitumor effects in GIST xenografts, and the effect was enhanced with ER stress-inducing drugs. ATF6 activation was frequently observed in 67% of patients with GIST (n = 42), and was significantly associated with poorer relapse-free survival (P = 0.033). Overall, GIST bypasses ER quality control (QC) and ER stress-mediated cell death via UPR activation and uses the QC-free Golgi to initiate signaling.

논문정보

형식Research article
게재일2023년 09월 (BRIC 등록일 2023-09-15)
연구진국내(교신)+국외 연구진
분야 생명과학 > 노화/암생물학

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