Panoply™ Human HDAC3 Knockdown Stable Cell Line

Histone deacetylases (HDACs) participate in the regulation of various cellular processes by modulating overall gene expression. Dysregulation of HDACs leads to cancer development, making them ideal targets for cancer therapy. However, clinical studies have shown that HDAC inhibitors (HDACi) alone have limited efficacy in treating solid tumors. Here, KDELR2 was identified as a novel target of HDAC3, and its aberrant expression is associated with poor prognosis in breast cancer patients. Researchers found a significant correlation between the protein expression patterns of HDAC3 and KDELR2 in breast cancer tumor tissues. ChIP assays and qRT-PCR analysis confirmed that HDAC3 transcriptionally activates KDELR2 via CREB1. The HDAC3-KDELR2 axis accelerates the cell cycle progression of cancer cells by protecting the centrosomal protein POC5 from proteasomal degradation. Furthermore, the HDAC3-KDELR2 axis promoted breast cancer cell proliferation and tumorigenesis both in vitro and in vivo. These findings reveal 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 therapeutic target for breast cancer.

Histone deacetylases (HDACs) are classified into four classes: Class I HDACs (HDAC1, 2, 3, and 8), Class II HDACs (Class IIa: HDAC4, 5, 7, and 9; Class IIb: HDAC6); nicotinamide adenine dinucleotide (NAD)-dependent class III HDACs (also called sirtuins); and Class IV HDACs (HDAC10, 11). To determine which Class I and Class II HDACs regulate KDELR2 expression, researchers first infected MDA-MB-231 cells with a mixed shRNA targeting Class I and Class II HDACs and found that KDELR2 mRNA levels were significantly reduced in cells with simultaneous knockdown of HDAC3 and HDAC8 compared to non-targeting control (NTC) cells (Figure 1A). Further studies revealed that HDAC3 (but not HDAC8) knockdown significantly reduced KDELR2 mRNA levels in MDA-MB-231 cells (Figure 1B-C). Western blotting analysis showed that KDELR2 protein levels were significantly reduced in HDAC3-knockdown MDA-MB-231 cells (Figure 1D). Consistent with this, forced expression of HDAC3 significantly increased KDELR2 mRNA expression (Figure 1E). Similar results were obtained in HDAC3-knockdown T47D cells. Therefore, HDAC3 was identified as the enzyme responsible for HDAC-mediated KDELR2 expression in breast cancer cells.

Figure 1. HDAC3 was responsible for HDACi-mediated KDELR2 expression. (Wei H, et al., 2021)