Abstract
Polycomb chromobox (CBX) proteins participate in the polycomb repressive complex (PRC1) that mediates epigenetic gene silencing and endows PRC1 with distinct oncogenic or tumor suppressor functions in a cell-type-dependent manner. In this study, we report that inhibition of cell migration, invasion, and metastasis in colorectal carcinoma requires CBX4-mediated repression of Runx2, a key transcription factor that promotes colorectal carcinoma metastasis. CBX4 inversely correlated with Runx2 expression in colorectal carcinoma tissues, and the combination of high CBX4 expression and low Runx2 expression significantly correlated with overall survival, more so than either CBX4 or Runx2 expression alone. Mechanistically, CBX4 maintained recruited histone deacetylase 3 (HDAC3) to the Runx2 promoter, which maintained a deacetylated histone H3K27 state to suppress Runx2 expression. This function of CBX4 was dependent on its interaction with HDAC3, but not on its SUMO E3 ligase, its chromodomain, or the PRC1 complex. Disrupting the CBX4-HDAC3 interaction abolished Runx2 inhibition as well as the inhibition of cell migration and invasion. Collectively, our data show that CBX4 may act as a tumor suppressor in colorectal carcinoma, and strategies that stabilize the interaction of CBX4 with HDAC3 may benefit the colorectal carcinoma patients with metastases. Cancer Res; 76(24); 7277-89. ©2016 AACR.
Highlights
Polycomb group (PcG) proteins have been documented to be major transcriptional repressors that mediate epigenetic gene silencing [1, 2]
CBX proteins may act as an oncogene or tumor suppressor in a cell-type–dependent manner [4], and we have recently reported that CBX8 exerts paradoxical effects in colorectal carcinoma, promoting proliferation while suppressing metastasis [10]
Knocking down CBX4 consistently increased the number of metastatic nodules and enhanced the tumor size (Fig. 1E and F) when HCT116 cells were injected into the tail veins of mice, and this increase was recapitulated in the hepatic metastasis in vivo animal model using these cells (Supplementary Fig. S4A and S4B)
Summary
Polycomb group (PcG) proteins have been documented to be major transcriptional repressors that mediate epigenetic gene silencing [1, 2]. PcG proteins organize to form two dominant polycomb -repressive complexes (PRC), PRC1 and PRC2 [3, 4], which are mainly involved in regulating development [5], senescence [6], stemness [7], and cancer progression [1, 4]. PcG proteins are well known to be frequently dysregulated in various cancer types [8]. Because PcG complexes contain multiple subunits and PcG proteins carry out various functions, the exact regulatory elements of PcG proteins that regulate certain types of cancer have not yet been identified [4]. Several polycomb chromobox (CBX) proteins, including CBX2, CBX4, CBX6, CBX7, and CBX8, have been shown to participate in the PRC1 complex and endow PRC1 with distinguish functions [9], suggesting that CBX proteins may act as an oncogene or tumor suppressor in a cell-type–dependent manner.
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