PGRMC1 promotes NSCLC stemness phenotypes by disrupting TRIM56-mediated ubiquitination of AHR

Anqi Guan; Ziyu Dai; Chen Jiang; Jingyi Sun; Baishuang Yang; Bin Xie; Qiong Chen

doi:10.1016/j.bbadis.2024.167440

PGRMC1 promotes NSCLC stemness phenotypes by disrupting TRIM56-mediated ubiquitination of AHR

Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167440. doi: 10.1016/j.bbadis.2024.167440. Epub 2024 Jul 24.

Authors

Anqi Guan¹, Ziyu Dai², Chen Jiang², Jingyi Sun², Baishuang Yang³, Bin Xie², Qiong Chen⁴

Affiliations

¹ Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China; Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, China.
² Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China.
³ Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
⁴ Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, China; Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China. Electronic address: qiongch@csu.edu.cn.

PMID: 39059592
DOI: 10.1016/j.bbadis.2024.167440

Abstract

Cancer stem cells (CSCs) are responsible for tumor chemoresistance, and the aryl hydrocarbon receptor (AHR) is indispensable for maintaining CSC characteristics. Here, we aimed to investigate how the interaction between progesterone receptor membrane component 1 (PGRMC1) and AHR contributes to the maintenance of CSC phenotypes in non-small cell lung cancer (NSCLC). Clinical data and tissue microarray analyses indicated that patients with elevated PGRMC1 expression had poorer prognoses. Moreover, PGRMC1 overexpression enhanced CSC phenotypes and chemotherapy resistance in vitro and in vivo by modulating AHR ubiquitination. We then determined the specific interaction sites between PGRMC1 and AHR. Mass spectrometry screening identified tripartite motif containing 56 (TRIM56) as the E3 ligase targeting AHR. Notably, PGRMC1 overexpression inhibited the interaction between TRIM56 and AHR. Overall, our study revealed a regulatory mechanism that involves PGRMC1, AHR, and TRIM56, providing insights for developing CSC-targeting strategies in NSCLC treatment.

Keywords: AHR; NSCLC; PGRMC1; Stemness; TRIM56; Ubiquitylation.

Publication types

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

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism
Carcinoma, Non-Small-Cell Lung* / genetics
Carcinoma, Non-Small-Cell Lung* / metabolism
Carcinoma, Non-Small-Cell Lung* / pathology
Cell Line, Tumor
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Male
Membrane Proteins* / genetics
Membrane Proteins* / metabolism
Mice
Mice, Nude
Neoplastic Stem Cells* / metabolism
Neoplastic Stem Cells* / pathology
Phenotype
Receptors, Aryl Hydrocarbon* / genetics
Receptors, Aryl Hydrocarbon* / metabolism
Receptors, Progesterone* / metabolism
Tripartite Motif Proteins* / genetics
Tripartite Motif Proteins* / metabolism
Ubiquitin-Protein Ligases* / genetics
Ubiquitin-Protein Ligases* / metabolism
Ubiquitination*

Substances

AHR protein, human
Basic Helix-Loop-Helix Transcription Factors
Membrane Proteins
PGRMC1 protein, human
Receptors, Aryl Hydrocarbon
Receptors, Progesterone
Tripartite Motif Proteins
Ubiquitin-Protein Ligases
TRIM56 protein, human