Upregulation of <scp>INHBA</scp> mediated by the transcription factor <scp>BHLHE40</scp> promotes colon cancer cell proliferation and migration

Wang, Jianan; Li, Bo; Yang, Shaohui; Ma, Chenyang; Liu, Kaitai; Chen, Xue; Cui, Wei

doi:10.1002/jcla.24539

Cited by 6 publications

(2 citation statements)

References 23 publications

(45 reference statements)

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“…To this end, we downregulated BHLHE40 with three different shRNAs and observed that this resulted in both reduced cell growth and clonogenic activity ( Figure 4 ). While this manuscript was under preparation, another study similarly showed that a BHLHE40 siRNA was capable of reducing HCT116 cell growth ( 62 ). These data implicate that BHLHE40 in its own right is a tumor promoter in colorectal cancer.…”

Section: Resultsmentioning

confidence: 96%

Promotion of colorectal cancer by transcription factor BHLHE40 involves upregulation of ADAM19 and KLF7

et al. 2023

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BHLHE40 is a transcription factor, whose role in colorectal cancer has remained elusive. We demonstrate that the BHLHE40 gene is upregulated in colorectal tumors. Transcription of BHLHE40 was jointly stimulated by the DNA-binding ETV1 protein and two associated histone demethylases, JMJD1A/KDM3A and JMJD2A/KDM4A, which were shown to also form complexes on their own and whose enzymatic activity was required for BHLHE40 upregulation. Chromatin immunoprecipitation assays revealed that ETV1, JMJD1A and JMJD2A interacted with several regions within the BHLHE40 gene promoter, suggesting that these three factors directly control BHLHE40 transcription. BHLHE40 downregulation suppressed both growth and clonogenic activity of human HCT116 colorectal cancer cells, strongly hinting at a pro-tumorigenic role of BHLHE40. Through RNA sequencing, the transcription factor KLF7 and the metalloproteinase ADAM19 were identified as putative BHLHE40 downstream effectors. Bioinformatic analyses showed that both KLF7 and ADAM19 are upregulated in colorectal tumors as well as associated with worse survival and their downregulation impaired HCT116 clonogenic activity. In addition, ADAM19, but not KLF7, downregulation reduced HCT116 cell growth. Overall, these data have revealed a ETV1/JMJD1A/JMJD2A→BHLHE40 axis that may stimulate colorectal tumorigenesis through upregulation of genes such as KLF7 and ADAM19, suggesting that targeting this axis represents a potential novel therapeutic avenue.

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Section: Resultsmentioning

confidence: 96%

Promotion of colorectal cancer by transcription factor BHLHE40 involves upregulation of ADAM19 and KLF7

et al. 2023

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“…We utilized the MEXPRESS database to uncover the methylation levels of INHBA in GC, but the results only revealed weak significant methylation level changes between tumor and normal tissues, suggesting that INHBA expression might not be controlled mainly by promoter methylation in GC, as seen in case of other tumors. Relevant studies have shown that there is a BHHE40 binding site near the INHBA promoter region, and the transcription factor BHLHE40 directly regulates the high expression of INHBA, thus promoting the proliferation and migration of colon cancer cells 48 . Other studies have shown that DNA amplification plays a key role in the upregulation of INHBA in patients with head and neck squamous cell carcinoma (HNSC).…”

Section: Discussionmentioning

confidence: 99%

Identification of INHBA as a potential biomarker for gastric cancer through a comprehensive analysis

Liu,

Shi

et al. 2023

Sci Rep

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Inhibin subunit beta A (INHBA) is a member of the transforming growth factor-beta (TGF-β) superfamily that plays a fundamental role in various cancers. However, a systematic analysis of the exact role of INHBA in patients with gastric cancer (GC) has not yet been conducted. We evaluated the expression levels of INHBA and the correlation between INHBA and GC prognosis in GC. The relationship between INHBA expression, immune infiltration levels, and type markers of immune cells in GC was also explored. In addition, we studied INHBA mutations, promoter methylation, and functional enrichment analysis. Besides, high expression levels of INHBA in GC were significantly related to unfavorable prognosis. INHBA was negatively correlated with B cell infiltration, but positively correlated with macrophage and most anticancer immunity steps. INHBA expression was positively correlated with the type markers of CD8+ T cells, neutrophils, macrophages, and dendritic cells. INHBA has a weak significant methylation level change between tumor and normal tissues and mainly enriched in cancer-related signaling pathways. The present study implies that INHBA may serve as a potential biomarker for predicting the prognosis of patients with GC. INHBA is a promising predictor of immunotherapy response, with higher levels of INHBA indicating greater sensitivity.

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Upregulation of INHBA mediated by the transcription factor BHLHE40 promotes colon cancer cell proliferation and migration

Wang

Yang

et al. 2022

Clinical Laboratory Analysis

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Background: Colon cancer is highly prevalent, and cell proliferation and migration are major reasons for its progression to malignancy. The upregulation of INHBA, a glycoprotein hormone that regulates the secretion of pituitary hormones, is documented to be oncogenic in numerous cancers, consisting of breast, gastric, and ovarian cancer. Herein, we assessed the role of INHBA in the proliferation along with the migration of colon cancer cells. Methods: TCGA datasets were used to assess INHBA expression and its correlation with prognosis in colon cancer patients. Analyses on JASPAR, PROMO, and ENCODE databases, uncovered high correlation between INHBA and BHLHE40. Western blot and RT-qPCR analysis were used to determine protein and mRNA levels. Cell transfection inhibited the expression of INHBA and BHLHE40. Cell proliferation rates were determined using CCK8 analysis. Wound healing assays were adopted to explore cell migration. Results: INHBA is markedly elevated in colon cancer tissues along with cells and is a predictive factor for patient's prognosis with colon cancer. INHBA silencing suppressed colon cancer cell proliferation and migration. Furthermore, we confirmed the association of INHBA with BHLHE40 in colon cancer cells. BHLHE40 could directly modulates INHBA expression. Here, we show that BHLHE40 modulates the expression of INHBA, which influences the proliferation, and migration of colon cancer cells. Conclusion: INHBA acts as an oncogene in colon cancer and it can be regulated by the transcription factor BHLHE40.

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Upregulation of INHBA mediated by the transcription factor BHLHE40 promotes colon cancer cell proliferation and migration

Cited by 6 publications

References 23 publications

Promotion of colorectal cancer by transcription factor BHLHE40 involves upregulation of ADAM19 and KLF7

Promotion of colorectal cancer by transcription factor BHLHE40 involves upregulation of ADAM19 and KLF7

Identification of INHBA as a potential biomarker for gastric cancer through a comprehensive analysis

Upregulation of INHBA mediated by the transcription factor BHLHE40 promotes colon cancer cell proliferation and migration

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