Chromobox 7/8 serve as independent indicators for glioblastoma via promoting proliferation and invasion of glioma cells

Abstract

BackgroundThe chromobox family, a critical component of epigenetic regulators, participates in the tumorigenesis and progression of many malignancies. However, the roles of the CBX family members (CBXs) in glioblastoma (GBM) remain unclear.MethodsThe mRNA expression of CBXs was analyzed in tissues and cell lines by Oncomine and Cancer Cell Line Encyclopedia (CCLE). The differential expression of CBXs at the mRNA level was explored in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases with the “beeswarm” R package. The protein expression of CBXs in GBM was further examined on Human Protein Atlas (HPA). The correlations between CBXs and IDH mutation and between CBXs and GBM subtypes were investigated in the TCGA portal and CGGA database with the “survminer” R package. The alteration of CBXs and their prognostic value were further determined via the cBioPortal and CGGA database with the “survival” R package. The univariate and multivariate analyses were performed to screen out the independent prognostic roles of CBXs in the CGGA database. Cytoscape was used to visualize the functions and related pathways of CBXs in GBM. U251 and U87 glioma cells with gene intervention were used to validate the role of CBX7/8 in tumor proliferation and invasion. Proliferation/invasion-related markers were conducted by Western blot and immunostaining.ResultsCBXs presented significantly differential expressions in pan-cancers. CBX2/3/5/8 were upregulated, whereas CBX6/7 were downregulated at mRNA level in GBM of TCGA and CGGA databases. Similarly, high expression of CBX2/3/5 and low expression of CBX6/8 were further confirmed at the protein level in the HPA. CBX2/6/7 were positively correlated with IDH mutation and CBX1/2/4/5/8 were closely related to GBM subtypes. CBX7 and CBX8 presented the independent prognostic factors for GBM patient survival. GO and KEGG analyses indicated that CBXs were closely related to the histone H3-K36, PcG protein complex, ATPase, and Wnt pathway. The overexpression of CBX7 and underexpression of CBX8 significantly inhibited the proliferation and invasion of glioma cells in vivo and in vitro.ConclusionOur results suggested that CBX7 and CBX8 served as independent prognostic indicators that promoted the proliferation and invasion of glioma cells, providing a promising strategy for diagnosing and treating GBM.

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

“…As a tumor suppressor, CBX7 is expressed at low levels in most tumors, such as glioma, HNSCC (71), EC (87,88), GC (93)(94)(95)(96)(97)(98), PAAD (109), CRC (103,104), clear cell renal cell carcinoma (ccRCC) (110), ovarian cancer (OC) (111), cervical carcinoma (CCA) (112) and skin cutaneous melanoma (SKCM) (113), while all CBX members, including CBX7 in hepatocellular carcinoma (HCC) (11,(114)(115)(116)(117)(118)(119)(120)(121)(122), have been proven to be tumor-promoting factors. The expression of CBX6 is different in different cancer types, with low expression in glioma (67,68), BC (77,80), CRC (103,104), ccRCC (110) and OC (111), but high expression in HNSCC (71), sarcoma (106) and SKCM (113). The results of studies on the expression of CBX in the same type of cancer are not completely consistent.…”

“…High expression of CBX2/3/8 in glioma (67,69), CBX2 in EC (89) and CBX1 in HCC (115) was indicated to lead to a high probability of tumor recurrence. In terms of other cancer characteristics, CBX2/6/7 is closely related to the isocitrate dehydrogenase mutation in glioma (68), CBX2 is related to a human epidermal growth factor receptor (EGFR)2-positive status of BC ( 74) and CBX3 is related to EGFR mutation in NSCLC (82). CBX1, CBX3 and CBX7 are also associated with vascular invasion in HCC (115), HNSCC (71) and CCA (112), respectively.…”

“…CBX6 may be either a poor prognostic factor or a favorable prognostic factor, depending on the type of cancer (67,77,94,(96)(97)(98)(99)103,110,117,122). CBX7 acts as a tumor suppressor in glioma (68), BC (15,77), LUAD (83,84,125), HCC (114,119), PAAD (99,109), ccRCC (110), CCA (112), sarcoma (106) and SKCM (113). When the expression of CBX7 is low, the OS of patients is shorter, but its relationship to survival in EC (86)(87)(88) and GC (94-98) is controversial.…”

Integrative Analysis of Genetic and Epigenetic Alterations in the CBX7 Gene Reveals Its Tumor-Suppressive Function by Regulating the Cell Cycle in Human Breast Cancer

“…Recent studies have revealed the distinct Integrative Analysis of Genetic and Epigenetic Alterations in the CBX7 Gene Reveals Oncol Insights.2023;2:691 functions among CBX family members in cancer. For example, CBX3 was found to be upregulated, whereas CBX7 was downregulated in many types of human cancer [14][15][16][17][18][19][20][21][22]. Some studies have shown that CBX3 transcriptionally suppresses the p21 gene to promote cell proliferation [23][24][25], while CBX7 transcriptionally suppresses CCNE1 expression to inhibit cell proliferation [26].…”

“…These studies indicate that some CBX genes function as oncogenes and others act as tumor suppressor genes. Moreover, the expression of many CBX genes has a prognostic impact on human cancer [14][15][16][17][18][19][20][21][22].…”