한빛사논문
- 조회884
Yuna Kim a,1, Kwan-Young Jung b,1, Yun Hak Kim c,d,1, Pan Xu e, Baeki E. Kang a, Yunju Jo f, Navin Pandit b, Jeongho Kwon a, Karim Gariani g, Joanna Gariani h, Junguee Lee i, Jef Verbeek j,k, Seungyoon Nam l,m, Sung-Jin Bae n, Ki-Tae Ha o, Hyon-Seung Yi p, Minho Shong q, Kyun-Hwan Kim a, Doyoun Kim b, Hee Jung Jung b, Chang-Woo Lee a, Kwang Rok Kim b, Kristina Schoonjans e, Johan Auwerx e, Dongryeol Ryu a,f
aDepartment of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
bTherapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea
cDepartment of Anatomy, School of Medicine, Pusan National University, Yangsan, Republic of Korea
dDepartment of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan, Republic of Korea
eLaboratory of Integrative Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland
fDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
gService of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, Geneva University Hospitals, Geneva, Switzerland
hDepartment of radiology, Hirslanden Grangettes Clinic, Geneva, Switzerland
iDepartment of Pathology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea
jLaboratory of Hepatology, Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Belgium
kDepartment of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium
lDepartment of Genome Medicine and Science, AI Convergence Center for Medical Science, Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea
mDepartment of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Republic of Korea
nDepartment of Molecular Biology and Immunology, Kosin University College of Medicine, Busan, Republic of Korea
oDepartment of Korean Medical Science, Pusan National University School of Korean Medicine, Yangsan, Republic of Korea
pLaboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, Republic of Korea
qResearch Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, Republic of Korea
1These authors contributed equally to this work.
Correspondence to: Yuna Kim, Kwang Rok Kim, Kristina Schoonjans, Johan Auwerx, Dongryeol Ryu
Abstract
Aims
Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance.
Methods
Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib.
Results
SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1β inhibition.
Conclusions
SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling.
논문정보
- Research article
- 2024년 01월 (BRIC 등록일 2024-01-29)
- 국내(교신)+국외 연구진
- 생명과학 > 노화/암생물학
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