Role of HOXA1-4 in the development of genetic and malignant diseases

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Abstract

The HOXA genes, belonging to the HOX family, encompass 11 members (HOXA1-11) and exert critical functions in early embryonic development, as well as various adult processes. Furthermore, dysregulation of HOXA genes is implicated in genetic diseases, heart disease, and various cancers. In this comprehensive overview, we primarily focused on the HOXA1-4 genes and their associated functions and diseases. Emphasis was placed on elucidating the impact of abnormal expression of these genes and highlighting their significance in maintaining optimal health and their involvement in the development of genetic and malignant diseases. Furthermore, we delved into their regulatory mechanisms, functional roles, and underlying biology and explored the therapeutic potential of targeting HOXA1-4 genes for the treatment of malignancies. Additionally, we explored the utility of HOXA1-4 genes as biomarkers for monitoring cancer recurrence and metastasis.

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Hepatocellular Carcinoma Detection by Plasma Methylated DNA: Discovery, Phase I Pilot, and Phase II Clinical Validation

John B Kisiel, Brian A Dukek, Reddappa V.S.R. Kanipakam … (2019)

Early detection improves hepatocellular carcinoma (HCC) outcomes, but better noninvasive surveillance tools are needed. We aimed to identify and validate methylated DNA markers (MDMs) for HCC detection. Reduced representation bisulfite sequencing was performed on DNA extracted from 18 HCC and 35 control tissues. Candidate MDMs were confirmed by quantitative methylation specific PCR in DNA from independent tissues (74 HCC, 29 controls). A phase I plasma pilot incorporated quantitative allele-specific real time target and signal amplification assays on independent plasma-extracted DNA from 21 HCC cases and 30 cirrhotic controls. A phase II plasma study was then performed in 95 HCC cases, 51 cirrhosis controls, and 98 healthy controls using target enrichment long-probe quantitative amplified signal (TELQAS) assays. Recursive partitioning identified best MDM combinations. The entire MDM panel was statistically cross-validated by randomly splitting the data 2:1 for training and testing. Random forest regression models performed on the training set predicted disease status in the testing set; the median AUC (and 95% CI) were reported after 500 iterations. In phase II, a 6-marker MDM panel (HOXA1, EMX1, AK055957, ECE1, PFKP and CLEC11A , normalized by B3GALT6 level yielded a best fit AUC of 0.96 (95% CI, 0.93–0.99) with HCC sensitivity of 95% (88–98%) at specificity of 92% (86–96%). The panel detected 3/4 (75%) stage 0, 39/42 (93%) stage A, 13/14 (93%) ge B, 28/28 (100%) stage C and 7/7 (100%) stage D HCC. The AUC value for AFP was 0.80 (0.74–0.87) compared to 0.94 (0.9–0.97) for the cross-validated MDM panel, P<0.0001. Novel MDMs identified in this study proved to accurately detect HCC via plasma testing. Further optimization and clinical testing of this promising approach are indicated.

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Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus

Qin Zhang, Gong-Hong Wei, Johanna Schleutker … (2018)

GWASs have identified rs11672691 at 19q13 associated with aggressive prostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2738 PCa patients, and discovered the biological mechanism underlying this association. We found an association of the aggressive PCa-associated allele G of rs11672691 with elevated mRNA levels of two biologically plausible candidate genes PCAT19 and CEACAM21 , implicating in PCa cell growth and tumor progression. Mechanistically, rs11672691 resides in an enhancer element and alters the binding site of HOXA2, a novel oncogenic transcription factor with prognostic potential in PCa. Remarkably, CRISPR/Cas9-mediated single nucleotide editing showed direct effect of rs11672691 on PCAT19 and CEACAM21 expression, and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and PCAT19/CEACAM21 gene expression on PCa prognosis. These results provide a plausible mechanism for rs11672691 associated with aggressive PCa, and hence lay the ground work for translating this finding to the clinic. A non-coding risk allele associated with aggressive prostate cancer creates a transcription factor binding site which in turn promotes oncogenesis by impacting expression of nearby genes

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Over-expressed lncRNA HOTAIRM1 promotes tumor growth and invasion through up-regulating HOXA1 and sequestering G9a/EZH2/Dnmts away from the HOXA1 gene in glioblastoma multiforme

Qi Li, Chengya Dong, Jiayue Cui … (2018)

Background Glioblastoma multiforme (GBM) is the common primary brain tumor classified the most malignant glioma. Long non-coding RNAs (LncRNAs) are important epigenetic regulators with critical roles in cancer initiation and progression. LncRNA HOTAIRM1 transcribes from the antisense strand of HOXA gene cluster which locus in chromosome 7p15.2. Recent studies have shown that HOTAIRM1 is involved in acute myeloid leukemia and colorectal cancer. Here we sought to investigate the role of HOTAIRM1 in GBM and explore its mechanisms of action. Methods The expressions of HOTAIRM1 and HOXA1 in GBM tissues and cells were determined by qRT-PCR, and the association between HOTAIRM1, HOXA1 transcription and tumor grade were analyzed. The biological function of HOTAIRM1 in GBM was evaluated both in vitro and in vivo. Chromatin immunoprecipitation (ChIP) assay and quantitative Sequenom MassARRAY methylation analysis were performed to explore whether HOTAIRM1 could regulate histone and DNA modification status of the HOXA1 gene transcription start sites (TSS) and activate its transcription. ChIP and RNA-ChIP were further performed to determine the molecular mechanism of HOTAIRM1 in epigenetic regulation of the HOXA1 gene. Results HOTAIRM1 was abnormally up-regulated in GBM tissues and cells, and this up-regulation was correlated with grade malignancy in glioma patients. HOTAIRM1 silencing caused tumor suppressive effects via inhibiting cell proliferation, migration and invasion, and inducing cell apoptosis. In vivo experiments showed knockdown of HOTAIRM1 lessened the tumor growth. Additionally, HOTAIRM1 action as regulating the expression of the HOXA1 gene. HOXA1, as an oncogene, it’s expression levels were markedly elevated in GBM tissues and cell lines. Mechanistically, HOTAIRM1 mediated demethylation of histone H3K9 and H3K27 and reduced DNA methylation levels by sequester epigenetic modifiers G9a and EZH2, which are H3K9me2 and H3K27me3 specific histone methyltransferases, and DNA methyltransferases (DnmTs) away from the TSS of HOXA1 gene. Conclusions We investigated the potential role of HOTAIRM1 to promote GBM cell proliferation, migration, invasion and inhibit cell apoptosis by epigenetic regulation of HOXA1 gene that can be targeted simultaneously to effectively treat GBM, thus putting forward a promising strategy for GBM treatment. Meanwhile, this finding provides an example of transcriptional control over the chromatin state of gene and may help explain the role of lncRNAs within the HOXA gene cluster. Electronic supplementary material The online version of this article (10.1186/s13046-018-0941-x) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Lumin Wang: wanglumin1@xjtu.edu.cn

Jinhai Wang: jinhaiwang@hotmail.com

Journal

Journal ID (nlm-ta): Biomark Res

Journal ID (iso-abbrev): Biomark Res

Title: Biomarker Research

Publisher: BioMed Central (London )

ISSN (Electronic): 2050-7771

Publication date (Electronic): 5 February 2024

Publication date PMC-release: 5 February 2024

Publication date Collection: 2024

Volume: 12

Electronic Location Identifier: 18

Affiliations

[1 ]Gastroenterology Department, The Second Affiliated Hospital of Xi’an Jiaotong University, ( https://ror.org/03aq7kf18) Xi’an, People’s Republic of China

[2 ]The Third Department of Medical Oncology, Shaanxi Provincial Cancer Hospital Affiliated to Medical College of Xi’an Jiaotong University, ( https://ror.org/017zhmm22) Xi’an, Shaanxi People’s Republic of China

[3 ]Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, ( https://ror.org/017zhmm22) Xi’an, Shaanxi People’s Republic of China

Article

Publisher ID: 569

DOI: 10.1186/s40364-024-00569-x

PMC ID: 10840290

PubMed ID: 38311789

SO-VID: 24b8e0bc-4c38-4d56-b10f-17ac598e7afd

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 30 October 2023

Date accepted : 20 January 2024

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100007128, Natural Science Foundation of Shaanxi Province;

Award ID: 2022JQ-842

Award Recipient : Lumin Wang

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Keywords: transcription factors,hoxa1-4,biomarkers,malignant diseases

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Keywords: transcription factors, hoxa1-4, biomarkers, malignant diseases

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Role of HOXA1-4 in the development of genetic and malignant diseases

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Most cited references 210

Hepatocellular Carcinoma Detection by Plasma Methylated DNA: Discovery, Phase I Pilot, and Phase II Clinical Validation

Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus

Over-expressed lncRNA HOTAIRM1 promotes tumor growth and invasion through up-regulating HOXA1 and sequestering G9a/EZH2/Dnmts away from the HOXA1 gene in glioblastoma multiforme

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