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

Abstract

HOX genes encode a family of evolutionarily conserved homeodomain transcription factors that are crucial both during development and adult life. In humans, 39 HOX genes are arranged in four clusters (HOXA, B, C, and D) in chromosomes 7, 17, 12 and 2, respectively. During embryonic development, particular epigenetic states accompany their expression along the anterior-posterior body axis. This tightly regulated temporal-spatial expression pattern reflects their relative chromosomal localization, and is critical for normal embryonic brain development, when HOX genes are mainly expressed in the hindbrain and mostly absent in the forebrain region. Epigenetic marks, mostly polycombassociated, are dynamically regulated at HOX loci and regulatory regions to ensure the finely tuned HOX activation and repression, highlighting a crucial epigenetic plasticity necessary for homeostatic development. HOX genes are essentially absent in healthy adult brain, whereas they are detected in malignant brain tumours, namely gliomas, where HOX genes display critical roles by regulating several hallmarks of cancer. Here, we review the major mechanisms involved in HOX genes (de)regulation in the brain, from embryonic to adult stages, in physiological and oncologic conditions. We focus particularly on the emerging causes of HOX gene deregulation in glioma, as well as on their functional and clinical implications.

Widespread overexpression from the four DNA hypermethylated HOX clusters in aggressive (IDHwt) glioma is associated with H3K27me3 depletion and alternative promoter usage

“…DNA methylation pattern alterations, a hallmark of cancer cells, could contribute to the observed HOX gene deregulation. However, while this mark represses promoter activity, HOX genes are documented to be hypermethylated in glioma samples [18]. Specifically, we previously observed that a class of genes characterized by an aberrant gain of both expression and DNA methylation at their CpG island (CGI) promoter in IDH wt glioma samples is precisely highly enriched for HOX genes [22].…”

“…In line with the absence of HOX gene expression in healthy brain, most HOX genes were upregulated, and only HOXD1 and HOXD‐AS1 , which are expressed in healthy brain, were downregulated in IDH wt samples. This observation suggests that deregulation affects all four HOX clusters and does not follow the coordinated collinear expression observed during normal embryonic development [18]. Given the key role of HOX transcription factors during normal development, it is reasonable to hypothesize that HOX gene upregulation contributes to gliomagenesis.…”

“…Aberrant HOX gene/protein expression is a hallmark of leukemia and of many solid cancer types, such as breast [9], bladder ( [10], kidney [11], and brain tumors, where HOX proteins can have oncogenic or tumor suppressor roles [12,13]. In glioma and particularly in GBM, many HOX factors are upregulated (transcript and protein level), suggesting that all four clusters are deregulated [14][15][16][17][18]. However, these findings are based on studies performed using different tumor samples or cancer cell lines and different methods to assess the expression.…”

HOXA5 Is Recognized as a Prognostic-Related Biomarker and Promotes Glioma Progression Through Affecting Cell Cycle

“…Other family members in the HOX family are also involved in tumor progression, including leukemia, breast cancer, lung cancer and so on (45,46). For instance, abnormal expressions of HOXA6, HOXA7, HOXA9, HOXA13, HOXB13, HOXD4, HOXD9, HOXD10, and HOXD13 were noticed in tumor tissue by comparing with normal tissue (47).…”

miR-615 Fine-Tunes Growth and Development and Has a Role in Cancer and in Neural Repair

“…Homeobox genes encode transcription factors that regulate the expression of several genes during embryogenesis [1]. Among them, Hox genes are very well described as specifying the anteroposterior pattern as well as the development of many organs [2], for example during neurodevelopment as well as in malignant glial tumors and as gliomas and glioblastomas [3]. Within this gene cluster, introns represent a hypothetically rich source of microRNAs (miRNAs).…”