HOXC10 promotes proliferation and invasion and induces immunosuppressive gene expression in glioma

Abstract

The prognosis for patients with malignant glioma is very poor and thus the identification of new potential therapeutic targets is critically important. In this work, we report a previously unknown role for the homeobox transcription factor HOXC10 in regulating immunosuppressive gene expression in glioma cell lines and their proliferative and invasive capacities. Although HOXC10 expression is dysregulated in several types of tumors, its potential function in glioma was not known. We found that HOXC10 expression was upregulated in glioma compared with normal tissue, and that HOXC10 expression positively associated with high grading of glioma. In three independent datasets (REMBRANDT glioma, The Cancer Genome Atlas glioblastoma multiforme and GSE4412), HOXC10 upregulation was associated with short overall survival. In two glioma cell lines, HOXC10 knock-down inhibited cell proliferation, colony formation, migration and invasion, and promoted apoptosis. In addition, HOXC10 knock-down suppressed the expression of genes that are involved in tumor immunosuppression, including those for transforming growth factor-β 2, PD-L2, CCL2 and TDO2. A ChIP assay showed that HOXC10 directly bound to the PD-L2 and TDO2 promoter regions. In summary, our results suggest that HOXC10 upregulation in glioma promotes an aggressive phenotype and induces immunosuppressive gene expression, supporting further investigation of the potential of HOXC10 as a therapeutic target in glioma.

Overexpression of HOXC10 promotes angiogenesis in human glioma via interaction with PRMT5 and upregulation of VEGFA expression

“…It has been reported that elevated expression of HOXC10 induced glioma proliferation, migration and invasion 26 . Therefore, we verified whether HOXC10 was upregulated in gliomas via analyzing public glioma datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO; GSE13276 and GSE4290).…”

“…Moreover, HOXC10 expression is dramatically elevated in lung adenocarcinoma compared to normal lung tissues and upregulation of HOXC10 correlated with unfavorable prognosis in patients with lung cancer 25 . Moreover, upregulated HOXC10 expression promotes proliferation, migration, and invasion in gliomas 26 . However, the precise biological role of HOXC10 in glioma angiogenesis remains largely undefined.…”

HOX gene cluster (de)regulation in brain: from neurodevelopment to malignant glial tumours

“…However, HOXA11 expression was significantly downregulated in recurrent GBMs compared with primary GBMs [147]. Several other studies also reported the overexpression of specific HOX genes in GBM compared with non-neoplastic brain samples: HOXA1 [148], HOXA9 [150], HOXA13 [146], HOXB3 [151], HOXB7 [152], HOXB9 [153], HOXC6 [154], HOXC9 [155], HOXC10 [156,157], HOXD4 [158], and HOXD9 [126]. Among these genes, HOXA1, HOXA9, HOXA13, HOXB9, and HOXC10 were expressed in a grade-dependent manner [148,150,146,153,156].…”

“…The genetic manipulation of HOXA5, A9, A10, A13, B3, B7, B9, C6, C9, C10, and D9 showed that their expression increases the viability of GBM cell lines [151,154,152,149,146,153,161,157,156,150,126,165,122], and five of them (HOXA9, A13, C6, C10, and D9) also reduce cell death [122,146,156,150,126,151]. HOXA7, A9, B7, B9, C9, and C10 also increased GBM cell lines migration capacity [166,152,153,157,156,150,165], while HOXA6, A13, B3, and B13 promoted increased invasion [166,152,153,157,167,156,150,151,165,146].…”

Oligonucleotide Therapeutics as a New Class of Drugs for Malignant Brain Tumors: Targeting mRNAs, Regulatory RNAs, Mutations, Combinations, and Beyond

“…Oligonucleotides may offer distinct advantages for targeting TFs, a feat that is especially difficult to achieve with small molecule inhibitors [ 112 ]. Candidate upregulated transcription factors include ZEB1, YAP/TAZ, MRTF-A, Gli-1, CREB, ETS-1, STAT3, TWIST1, HOXC10, EZH2, BMI1, JMJD6, P53, ATF5, REST, SP1, and NFAT [ 112 – 128 ], whereas others such as KLF6 are downregulated [ 129 ]. ELK4 downregulation was shown to reduce Mcl-1, an anti-apoptotic protein in GBM, resulting in reduced tumor formation in xenograft models.…”