C1QL1 inhibits breast cancer through the HSP90α/VCP-ERS/UPR axis

Exp Mol Med. 2025 Jun;57(6):1308-1323. doi: 10.1038/s12276-025-01486-1.

Ningning Zhang ^# ¹ ², Qing Shao ^# ¹, Xinni Xiang ³, Chun Yan ⁴, Dan Tao ² ⁵, Qian Li ⁶, Huan Rong ², Yi Zhao ², Tingxiu Xiang ⁷, Xiaohua Zeng ⁸ ⁹

Affiliations

1 Department of Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China.
2 Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China.
3 West China School of Medicine, Sichuan University, Chengdu, China.
4 Department of Medical Aesthetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
5 Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China.
6 Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
7 Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China. xiangtx@cqmu.edu.cn.
8 Department of Breast Cancer Center, Chongqing University Cancer Hospital, Chongqing, China. zxiaohuacqu@126.com.
9 Chongqing Key Laboratory for Intelligent Oncology in Breast Cancer (iCQBC), Chongqing University Cancer Hospital, Chongqing, China. zxiaohuacqu@126.com.
# Contributed equally.

PMID: 40583061 DOI: 10.1038/s12276-025-01486-1

Abstract

Our earlier research discovered that C1QL1 was expressed less in breast Cancer (BrCa) tissues than in normal breast tissues by analyzing the gene profile of RNA sequences. However, up to now, the biological function of C1QL1 and its molecular mechanism in BrCa remains unknown. Here public database analyses, quantitative PCR with reverse transcription, western blot, immunohistochemistry and quantitative methylation-specific PCR were used to analyze C1QL1 expression and promoter methylation. The effects of C1QL1 on BrCa proliferation, cell cycle, Apoptosis and metastasis were assessed using the Cell Counting Kit-8, flow cytometry analysis, terminal deoxynucleotidyl transferase dUTP nick end labeling assays, transwell in vitro and nude mice experiments in vivo. Liquid chromatography-tandem mass spectrometry, co-immunoprecipitation and western blot were performed to identify factors that mediate the effects of C1QL1. In BrCa, C1QL1 is often silenced due to promoter methylation, and its expression is favorably connected with prognosis. Overexpression of C1QL1 inhibits BrCa cell proliferation, metastasis and promotes Cancer cell Apoptosis both in vitro and in vivo. Conversely, C1QL1 knockdown increases the proliferation and spread of BrCa cells. Mechanistically, C1QL1 is located at endoplasmic reticulum and interacts with HSP90α and VCP to facilitate their ubiquitin-mediated degradation. This leads to the caspase-dependent Apoptosis that occurs in BrCa cells as a result of ER stress (ERS)/unfolded protein response (UPR). Our results support that C1QL1 can act as a tumor suppressor of BrCa by modulating the C1QL1/HSP90α/VCP-ERS/UPR pathway, implying that the promoter methylation status of C1QL1 or the expression of C1QL1 may represent a potential marker for the diagnosis or prognosis of BrCa.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-12861

CB-5083

99.90%, p97 AAA ATPase/VCP Inhibitor

p97

Cancer
HY-13468

KW-2478

99.53%, HSP Inhibitor

HSP

Cancer

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