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KDELR2 promotes breast cancer proliferation via HDAC3-mediated cell cycle progression

Haoran Wei¹, Wenhao Ma¹, Xiaofei Lu¹

¹Hefei National Laboratory for Physical Sciences at Microscale, the Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, P. R. China.

Cancer Communications (London, England)

|June 19, 2021

Abstract

Background:

Histone deacetylases (HDACs) engage in the regulation of various cellular processes by controlling global gene expression. The dysregulation of HDACs leads to carcinogenesis, making HDACs ideal targets for cancer therapy. However, the use of HDAC inhibitors (HDACi) as single agents has been shown to have limited success in treating solid tumors in clinical studies. This study aimed to identify a novel downstream effector of HDACs to provide a potential target for combination therapy.

Methods:

Transcriptome sequencing and bioinformatics analysis were performed to screen for genes responsive to HDACi in breast cancer cells. The effects of HDACi on cell viability were detected using the MTT assay. The mRNA and protein levels of genes were determined by quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. Cell cycle distribution and apoptosis were analyzed by flow cytometry. The binding of CREB1 (cAMP-response element binding protein 1) to the promoter of the KDELR (The KDEL (Lys-Asp-Glu-Leu) receptor) gene was validated by the ChIP (chromatin immunoprecipitation assay). The association between KDELR2 and protein of centriole 5 (POC5) was detected by immunoprecipitation. A breast cancer-bearing mouse model was employed to analyze the effect of the HDAC3-KDELR2 axis on tumor growth.

Results:

KDELR2 was identified as a novel target of HDAC3, and its aberrant expression indicated the poor prognosis of breast cancer patients. We found a strong correlation between the protein expression patterns of HADC3 and KDELR2 in tumor tissues from breast cancer patients. The results of the ChIP assay and qRT-PCR analysis validated that HDAC3 transactivated KDELR2 via CREB1. The HDAC3-KDELR2 axis accelerated the cell cycle progression of cancer cells by protecting the centrosomal protein POC5 from proteasomal degradation. Moreover, the HDAC3-KDELR2 axis promoted breast cancer cell proliferation and tumorigenesis in vitro and in vivo.

Conclusion:

Our results uncovered a previously unappreciated function of KDELR2 in tumorigenesis, linking a critical Golgi-the endoplasmic reticulum traffic transport protein to HDAC-controlled cell cycle progression on the path of cancer development and thus revealing a potential therapeutical target for breast cancer.

Insights

Histone deacetylases (HDACs) regulate gene expression and are cancer targets. This study identified KDELR2 as a novel HDAC3 target, revealing the HDAC3-KDELR2 axis promotes breast cancer progression and offers a potential therapeutic target.

Area of Science:

Molecular Biology
Cancer Biology
Cell Biology

Background:

Histone deacetylases (HDACs) regulate gene expression and are implicated in carcinogenesis.
HDAC inhibitors (HDACi) show limited efficacy as single agents for solid tumors.
Identifying novel HDAC targets is crucial for developing effective combination therapies.

Purpose of the Study:

To identify novel downstream effectors of HDACs in breast cancer.
To investigate the role of the identified effector in tumorigenesis.
To explore the potential of this effector as a therapeutic target for combination therapy.

Main Methods:

Transcriptome sequencing and bioinformatics analysis to screen for HDACi-responsive genes.
Cell viability assays (MTT), qRT-PCR, and Western blotting to assess gene expression.
Flow cytometry for cell cycle and apoptosis analysis; ChIP and co-immunoprecipitation to validate interactions.
In vitro and in vivo (mouse model) studies to evaluate the therapeutic target's effect on tumor growth.

Main Results:

KDELR2 was identified as a novel target of HDAC3, with its aberrant expression correlating with poor breast cancer prognosis.
HDAC3 was shown to transactivate KDELR2 expression via CREB1, establishing the HDAC3-KDELR2 axis.
This axis accelerates cell cycle progression by protecting POC5 from degradation, promoting breast cancer proliferation and tumorigenesis.

Conclusions:

KDELR2 plays a previously unrecognized role in tumorigenesis.
The Golgi-endoplasmic reticulum traffic protein KDELR2 links HDAC-controlled cell cycle progression to cancer development.
The HDAC3-KDELR2 axis represents a potential therapeutic target for breast cancer treatment.

Read full analysis

Keywords:

CREB1 HADC3 KDELR2 breast cancer histone deacetylase inhibitor protein of centriole 5

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