Gene expression signatures for HOXA4, HOXA9, and HOXD10 reveal alterations in transcriptional regulatory networks in colon cancer

Abstract

We previously reported that HOXA4, HOXA9, and HOXD10 are selectively expressed in colonic stem cells (SCs) and their overexpression contributes to colorectal cancer (CRC). Our goals here were to determine how these HOX genes are transcriptionally regulated and whether transcriptional dysregulation of HOX genes occurs in CRC. Accordingly, we used correlation analysis to identify genes that are expression‐correlated or anticorrelated with HOXA4, HOXA9, and HOXD10. We then used Gene Ontology (GO) analysis to functionally classify these genes. The GO results for both HOXA4 and HOXD10 correlated gene sets for normal colon and CRC show functions mostly classified as developmental, transcriptional regulation, and DNA binding. This raised the question: Are these gene sets regulated by the same transcription factors (TFs)? Consequently, we used promoter analysis and interaction network toolset (PAINT) to identify commonly shared transcription response elements. The results indicated that completely different sets of TFs coregulate HOXA4 and HOXD10 (but not HOXA9) and their expression‐correlated genes. And predicted TFs are altered in CRC compared with normal colon. Taken together, analysis of gene signatures correlated with expression of HOXA4 and HOXD10 indicates how these HOX genes are: (a) transcriptionally regulated in the normal colon; (b) dysregulated in CRC. This discovery provides a mechanism for targeting CRC SCs.

miR‑429 inhibits osteosarcoma progression by targeting HOXA9 through suppressing Wnt/β‑catenin signaling pathway

“…Moreover, it was found that HOXA9 acted as an oncogene in OS development. These findings are consistent with previous research that HOXA9 level is increased markedly in ovarian cancer patients (41) and it was upregulated in colon cancer (42). The higher expression of HOXA9 was associated with OS tumor size, TNM stage and clinical stage.…”

Aldehyde dehydrogenase 1A1 and 1A3 isoforms – mechanism of activation and regulation in cancer

“…Same as the homeotic genes, retinoids could control the expression of Hox genes. Langston et al [89] identified RARE as part of the regulatory regions of Hox genes and demonstrated the possibility of influencing their transcription by RA. There is reciprocal feedback between HOXA5 and Wnt signalling.…”

A Case of Identity: HOX Genes in Normal and Cancer Stem Cells

“…Further studies have shown the role of HOX genes in CSC transformation. For instance, HOXA4 and HOXA9 are enriched during the transformation of colon CSC, and their expression contributes to sustained CSC self-renewal [81]. Upregulation of HOXA9 has also been shown to sustain the self-renewal of HSC in acute myeloid leukemia (AML) and the NUP98-HOXA9 fusion protein induces long-term proliferation and impaired differentiation of leukemic CSC [82,83].…”