김윤정 (충남대학교 의과대학)

한빛사논문

조회360

충남대학교 의과대학

Exp. Mol. Med., Mar 05 2024, | https://doi.org/10.1038/s12276-024-01194-2 SIRT1 ISGylation accelerates tumor progression by unleashing SIRT1 from the inactive state to promote its deacetylase activity

Ji An Kang^1,2,3,13, Yoon Jung Kim^1,2,3,13, Kyu Yun Jang⁴, Hye Won Moon^1,3, Haeseung Lee⁵, Seonjeong Lee^6,7, Hyun Kyu Song⁸, Sang Woo Cho⁹, Yoon Sun Yoo^1,3, Hye Gyeong Han^1,3, Min-Ju Kim⁵, Myoung Ja Chung⁴, Cheol Yong Choi⁹, Cheolju Lee^6,7, Chaeuk Chung¹⁰, Gang Min Hur¹¹, You-Sun Kim¹²and Young Joo Jeon^1,3

¹Department of Biochemistry, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea.

²Brain Korea 21 FOUR Project for Medical Science, Chungnam National University, Daejeon 35015, Republic of Korea.

³Department of Medical Science, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea.

⁴Department of Pathology, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital and Research Institute for Endocrine Sciences, Jeonju 54896, Republic of Korea.

⁵College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.

⁶Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.

⁷Division of BioMedical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea.

⁸Department of Life Sciences, Korea University, Seoul 02841, Republic of Korea.

⁹Department of Biological Sciences, Sungkyunkwan University, Suwon 16419, Republic of Korea.

¹⁰Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 34134, Republic of Korea.

¹¹Department of Pharmacology, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea.

¹²Department of Biochemistry, Ajou University, School of Medicine & Department of Biomedical Sciences, Graduate School, Ajou University, Suwon 16499, Republic of Korea.

¹³These authors contributed equally: Ji An Kang, Yoon Jung Kim.

Corresponding author : Correspondence to Young Joo Jeon.

Abstract

ISG15 is an interferon-stimulated ubiquitin-like protein (UBL) with multifaceted roles as a posttranslational modifier in ISG15 conjugation (ISGylation). However, the mechanistic consequences of ISGylation in cancer have not been fully elucidated, largely due to a lack of knowledge on the ISG15 target repertoire. Here, we identified SIRT1, a nicotinamide adenine dinucleotide (NAD ⁺)-dependent protein deacetylase, as a new target for ISGylation. SIRT1 ISGylation impairs the association of SIRT1 with its negative regulator, deleted in breast cancer 1 (DBC1), which unleashes SIRT1 from its inactive state and leads to an increase in its deacetylase activity. Importantly, SIRT1 ISGylation promoted lung cancer progression and limited lung cancer cell sensitivity to DNA damage-based therapeutics in vivo and in vitro models. The levels of ISG15 mRNA and protein were significantly higher in lung cancer tissues than in adjacent normal tissues. Accordingly, elevated expression of SIRT1 and ISG15 was associated with poor prognosis in lung cancer patients, a finding that could be translated for lung cancer patient stratification and disease outcome evaluation. Taken together, our findings provide a mechanistic understanding of the regulatory effect of SIRT1 ISGylation on tumor progression and therapeutic efficacy in lung cancer.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-03-07)
연구진국내 연구진
분야 의약학 > 분자세포의학

댓글 작성 로그인

CV 열람하기

연락처 보기