LncRNA RGMB-AS1 inhibits HMOX1 ubiquitination and NAA10 activation to induce ferroptosis in non-small cell lung cancer

Gui-Bin Gao; Liang Chen; Jia-Feng Pan; Tao Lei; Xin Cai; Zhexue Hao; Qi Wang; Ge Shan; Jin Li

doi:10.1016/j.canlet.2024.216826

LncRNA RGMB-AS1 inhibits HMOX1 ubiquitination and NAA10 activation to induce ferroptosis in non-small cell lung cancer

Cancer Lett. 2024 May 28:590:216826. doi: 10.1016/j.canlet.2024.216826. Epub 2024 Apr 2.

Authors

Gui-Bin Gao¹, Liang Chen², Jia-Feng Pan¹, Tao Lei¹, Xin Cai¹, Zhexue Hao³, Qi Wang¹, Ge Shan⁴, Jin Li⁵

Affiliations

¹ The Key Laboratory of Advanced Interdisciplinary Studies, The State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510530, China.
² Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, 230027, China.
³ Department of Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510530, China.
⁴ Department of Laboratory Medicine, The First Affiliated Hospital of USTC, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Science, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, 230027, China.
⁵ The Key Laboratory of Advanced Interdisciplinary Studies, The State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510530, China; Department of Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510530, China; The People's Hospital of Anshun City, Anshun, Guizhou, 561000, China. Electronic address: JL@gzlab.ac.cn.

PMID: 38574881
DOI: 10.1016/j.canlet.2024.216826

Abstract

Ferroptosis, an iron-dependent regulated cell death caused by excessive lipid peroxide accumulation, has emerged as a promising therapeutic target in various cancers, including non-small cell lung cancer (NSCLC). In this study, we identified the long non-coding RNA RGMB-AS1 as a key regulator of ferroptosis in NSCLC. Mechanistically, RGMB-AS1 interacted with heme oxygenase 1 (HMOX1) and prevented its ubiquitination by the E3 ligase TRC8, leading to increased HMOX1 stability and enhanced ferroptosis. Additionally, RGMB-AS1 bound to the 82-87 amino acid region of N-alpha-acetyltransferase 10 (NAA10), stimulating its acetyltransferase activity and promoting the conversion of acetyl-CoA to HMG-CoA, further contributing to ferroptosis. The RGMB-AS1-HMOX1 and RGMB-AS1-NAA10 axes synergistically inhibited NSCLC growth both in vitro and in vivo. Clinically, low RGMB-AS1 expression was associated with advanced tumor stage and poor overall survival in NSCLC patients. Furthermore, adeno-associated virus-mediated RGMB-AS1 overexpression significantly suppressed tumor growth in mouse xenograft models. Our findings uncover a novel lncRNA-mediated regulatory mechanism of ferroptosis and highlight the potential of RGMB-AS1 as a prognostic biomarker and therapeutic target in NSCLC.

Keywords: Ferroptosis; HMOX1; NAA10; Non-small cell lung cancer; RGMB-AS1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Animals
Carcinoma, Non-Small-Cell Lung* / genetics
Carcinoma, Non-Small-Cell Lung* / metabolism
Carcinoma, Non-Small-Cell Lung* / pathology
Cell Line, Tumor
Cell Proliferation
Female
Ferroptosis* / genetics
Gene Expression Regulation, Neoplastic
Heme Oxygenase-1* / genetics
Heme Oxygenase-1* / metabolism
Humans
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Male
Mice
Mice, Nude
RNA, Long Noncoding* / genetics
RNA, Long Noncoding* / metabolism
Ubiquitination*
Xenograft Model Antitumor Assays

Substances

RNA, Long Noncoding
Heme Oxygenase-1
HMOX1 protein, human