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