HOXB9 acetylation at K27 is responsible for its suppression of colon cancer progression

Song, Jianguo; Wang, Tianzhuo; Xu, Weizhi; Wang, Peng; Wan, Junhu; Wang, Yunling; Zhan, Jun; Zhang, Hongquan

doi:10.1016/j.canlet.2018.04.002

Cited by 25 publications

(38 citation statements)

References 36 publications

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“… 47 However, the molecular mechanisms by which HOXB9 contributes to carcinogenesis are debated. 48 , 49 The overexpression of HOXB9 can suppress the AKT/NF-κB/Snail pathway and inhibit the proliferation of gastric carcinoma cells. 50 We analyzed the correlation between EGFR signaling and NF-κB–dependent pathways (GSE60644) and found that expression of HOXB9 negatively associated with that of KIAA1199 (Cell migration–inducing hyaluronidase 1; Data Supplement).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Epigenetic Landscape of Lung Adenocarcinoma Links HOXB9 DNA Methylation to Intrinsic EGFR-TKI Resistance and Heterogeneous Responses

Liu

Cheng

et al. 2021

JCO Precision Oncology

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PURPOSE Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) show efficacy in treating patients with lung adenocarcinoma with EGFR-activating mutations. However, a significant subset of targeted patients fail to respond. Unlike acquired resistance (AR), intrinsic resistance (IR) remains poorly understood. We investigated whether epigenomic factors contribute to patient-to-patient heterogeneity in the EGFR-TKI response and aimed to characterize the IR subpopulation that obtains no benefit from EGFR-TKIs. PATIENTS AND METHODS We conducted genome-wide DNA methylation profiling of 79 tumors sampled from patients with advanced lung adenocarcinoma before they received EGFR-TKI treatment and analyzed the patient responses. Pyrosequencing was performed in a validation cohort of 163 patients with EGFR-activating mutations. RESULTS A DNA methylation landscape of 216 CpG sites with differential methylation was established to elucidate the association of DNA methylation with the characteristics and EGFR-TKI response status of the patients. Functional analysis of 37 transcription-repressive sites identified the enrichment of transcription factors, notably homeobox ( HOX) genes. DNA methylation of HOXB9 (cg13643585) in the enhancer region yielded 88% sensitivity for predicting drug response (odds ratio [OR], 6.64; 95% CI, 1.98 to 25.23; P = .0009). Pyrosequencing validated that HOXB9 gained methylation in patients with a poor EGFR-TKI response (OR, 3.06; 95% CI, 1.13 to 8.19; P = .019). CONCLUSION Our data suggest that homeobox DNA methylation could be a novel tumor cellular state that can aid the precise categorization of tumor heterogeneity in the study of IR to EGFR-TKIs. We identified, for the first time, an epigenomic factor that can potentially complement DNA mutation status in discriminating patients with lung adenocarcinoma who are less likely to benefit from EGFR-TKI treatment, thereby leading to improved patient management in precision medicine.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Epigenetic Landscape of Lung Adenocarcinoma Links HOXB9 DNA Methylation to Intrinsic EGFR-TKI Resistance and Heterogeneous Responses

Liu

Cheng

et al. 2021

JCO Precision Oncology

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“…It is noteworthy that the aberrant expression of HOX genes has been shown to contribute to cancer progression and development (33,34). Indeed, it has been observed that HOX genes exhibit a dysregulated expression in leukemia, ovarian and lung cancer (35)(36)(37)(38). The function of HOXB9 novel tumor suppressor in the regulation of colon adenocarcinoma progression has also been identified (39).…”

Section: Discussionmentioning

confidence: 99%

Analysis of TCGA data of differentially expressed EMT‑related genes and miRNAs across various malignancies to identify potential biomarkers

et al. 2020

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Tumor heterogeneity presents a hindering factor that leads to therapeutic failures and limits the improvement of clinical outcomes within the concept of precision medicine. This heterogenous characteristic provides the epithelial mesenchymal plasticity that is considered an advantage for cancer cell metabolism and genome function to be adjusted within the microenvironment, and also plays a role in the development of drug resistance and metastasis. To this respect, identifying druggable molecular targets that modulate signaling networks, which contribute to cancer cell heterogeneity, could provide innovative therapeutics with improved safety and efficacy profiles. The present study attempted to identify potentially druggable molecular targets that have been connected to the process of epithelial-to-mesenchymal transition (EMT). Towards this goal, gene and miRNA differential expression analyses were performed for cancer patients with 4 and 3 different tumor types, respectively, using data that were retrieved from The Cancer Genome Atlas (TCGA) program. Furthermore, the dbEMT 1.0 database was used to limit the results to differentially expressed molecular targets that have already been associated with EMT. The analysis resulted in the identification of multiple EMT-associated genes and miRNAs for all types of cancer, which, through pairwise comparisons, were separated into groups of common potential targets for different malignancies. Differential gene expression profiling by RT-qPCR analysis was also carried out for a number of selected genes and miR-21 in human cancer cell lines. Notably, EMT-associated homeobox B9 (HOXB9) and miR-137 were found to have a deregulated expression in all malignancies examined, thus increasing their potential as druggable targets for cancer therapy. Overall, the present study presents an approach that, through systematic in silico analysis, could lead to the selection of potential druggable biomarkers of broader utility for several tumor types, irrespective of their tissue of origin.

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“…A total of 3003 patients with stage I-IV CRC between 20 and 90 years old were included in the studies All 25 studies were single-centre and were published between 1997 and 2020. Two studies included patients who either received or not neoadjuvant chemotherapy [24,25], 5 studies included only patients without neoadjuvant chemotherapy [23,26,27,29,42] whereas in the remaining studies no information on the chemotherapy status was available. Differential HOX gene expression between cancer and normal tissue was reported by 22 studies [21-23, 25-28, 30-34, 36-45].…”

Section: Study Characteristicsmentioning

confidence: 99%

The Role of HOX Genes as Potential Biomarkers in Colorectal Cancer: A Systematic Review

Martinou¹,

Falgari²,

Angelidi³

et al. 2021

Preprint

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Background: Colorectal cancer (CRC) is worldwide the third leading cause of cancer-related death, and despite therapeutic advances, survival remains low. Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This systematic review aims to present the current evidence on the role of HOX genes as biomarkers in CRC and the impact of their modulation in tumour growth and progression. Methods: MEDLINE, EMBASE, Web of Science and Cochrane databases were searched by following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Eligible studies investigated two research questions: a) the clinicopathological and prognostic significance of HOX gene dysregulation in patients with CRC and b) the functional role of HOX genes in CRC progression. This study was registered in the international prospective register of systematic reviews (PROSPERO), CRD42020190953. Results: Twenty-five studies enrolling 3003 patients with stage I-IV CRC, showed that 26 out of 39 HOX genes were dysregulated in cancerous versus normal colon. Aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. Conclusions: In conclusion, our findings suggest that HOX proteins play vital roles in CRC progression and significantly affect survival. Further research, though, is required to elucidate their potential role as biomarkers in CRC.

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HOXB9 acetylation at K27 is responsible for its suppression of colon cancer progression

Cited by 25 publications

References 36 publications

Genome-Wide Epigenetic Landscape of Lung Adenocarcinoma Links HOXB9 DNA Methylation to Intrinsic EGFR-TKI Resistance and Heterogeneous Responses

Genome-Wide Epigenetic Landscape of Lung Adenocarcinoma Links HOXB9 DNA Methylation to Intrinsic EGFR-TKI Resistance and Heterogeneous Responses

Analysis of TCGA data of differentially expressed EMT‑related genes and miRNAs across various malignancies to identify potential biomarkers

The Role of HOX Genes as Potential Biomarkers in Colorectal Cancer: A Systematic Review

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