CBX8 Together with SET Facilitates Ovarian Carcinoma Growth and Metastasis by Suppressing the Transcription of SUSD2

Abstract

Polycomb group proteins are often dysregulated in cancer, leading to disruption of epigenetic landscapes and acquisition of cancer hallmarks. Chromobox 8 (CBX8) is a core component of canonical polycomb repressive complex 1, however, its role in transcriptional regulation and in ovarian carcinoma progression has not been extensively investigated. In this study, we find that CBX8 is up-regulated in ovarian cancer. Overexpression and knockdown approaches show that CBX8 facilitates the growth and migration of CAOV3, A2780, and SKOV3 cells in vitro. Consistently, depletion of CBX8 suppresses the growth and metastasis of ovarian carcinoma in vivo. Mechanistically, RNA-seq assays together with functional rescue experiments identify a tumor suppressor, SUSD2, as the functional target of CBX8 in ovarian carcinoma cells. Significantly, FLAG affinity coupled with mass spectrometry discovers that CBX8 interacts with a subunit of inhibitor of acetyltransferases (INHAT), SET, which also promotes the growth and migration of A2780 cells. CBX8 and SET co-bind to the promoter of SUSD2 to establish H2AK119ub1 and prevent the acetylation of histone H3, resulting in transcriptional suppression of SUSD2. Implications: Our study uncovers a novel mechanism CBX8 explores to execute gene repression, and provides new therapeutic targets for ovarian carcinoma.

Key chromatin regulator-related genes associated with the risk of coronary artery disease regulate the expression of HCFC1, RNF8, TNP1 and SET

“…The versatile protein SET is involved in multiple cellular functions, such as apoptosis, transcription, nucleosome assembly, and histone chaperoning [ 29 ]. Isoform 2 of SET functions to inhibit apoptosis by blocking the activity of GZMA-activated DNase NME1.During cytotoxic T lymphocyte-induced cell death, GZMA cuts SET, breaking its connection with NME1 and releasing the suppression of NME1 [ 29 ].…”

“…The versatile protein SET is involved in multiple cellular functions, such as apoptosis, transcription, nucleosome assembly, and histone chaperoning [ 29 ]. Isoform 2 of SET functions to inhibit apoptosis by blocking the activity of GZMA-activated DNase NME1.During cytotoxic T lymphocyte-induced cell death, GZMA cuts SET, breaking its connection with NME1 and releasing the suppression of NME1 [ 29 ]. Both isoforms 1 and 2 function as strong blockers of phosphatase 2A.Isoforms 1 and 2 also hinder EP300/CREBBP- and PCAF-mediated histone acetyltransferases and nucleosomes, possibly by blocking the access of histone lysine residues to acetylases [ 30 ].…”

CBX8 promotes lung adenocarcinoma growth and metastasis through transcriptional repression of CDKN2C and SCEL

“…CBX8 is involved in the progression of glioblastoma and breast cancer (Jia et al, 2020). Our previous work has demonstrated that CBX8, together with SET, promotes ovarian carcinoma growth and metastasis by downregulating SUSD2 expression (Creppe et al, 2014; Wu et al, 2022). To gain a comprehensive understanding of different functions of CBX proteins in cancer progression, we investigated the mRNA expression of these five CBX family genes across multiple cancers using TCGA data set.…”

Chromobox proteins in cancer: Multifaceted functions and strategies for modulation (Review)

“…Overexpression and knockdown experiments have indicated that CBX8 promotes the growth and migration of OC cells in vitro. Mechanistically, CBX8 and SE translocation protein (SET) bind the promoter of sushi domain containing 2 (SUSD2) to establish H2AK119ub1 and block the acetylation of histone H3, resulting in the transcriptional inhibition of SUSD2 (136). 135) interacting with HDAC2 to increase the acetylation of histone H3 and H4 at the E-cadherin promoter OC Growth; migration CBX8 and SET bind to the promoter of SUSD2 to establish (136) H2AK119ub1 and block the acetylation of histone H3, resulting in transcriptional inhibition of SUSD2 CBX, chromobox; PCa, prostate carcinoma; GC, gastric cancer; CCCA, cholangiocellular carcinoma; NEPC, neuroendocrine prostate cancer; BC, breast cancer; HCC, hepatocellular carcinoma; CRC, colorectal cancer; ccRCC, clear cell renal cell carcinoma; TCA, thyroid carcinoma; OC, ovarian cancer; EMT, epithelial to mesenchymal transition; H3K9, histone H3 lysine K9; H3K4me3, histone H3 lysine K4 trimethylation; CDC20, cell division cycle 20; SFRP1, secreted frizzled-related protein 1; AR, androgen receptor; RE1, repressor element-1; TF, transcription factor; BMP4, bone morphogenetic protein 4; RUNX2, runt-related transcription factor 2; HDAC, histone deacetylase; KLF6, Kruppel-like factor 6; SET, SE translocation protein; SUSD2, sushi domain containing 2; H2AK119ub1, monoubiquitination of histone H2A lysine 119.…”