JMJD1A, H3K9me1, H3K9me2 and ADM expression as prognostic markers in oral and oropharyngeal squamous cell carcinoma

<div><p>Aims</p><p>Jumonji Domain-Containing 1A (JMJD1A) protein promotes demethylation of histones, especially at lysin-9 of di-methylated histone H3 (H3K9me2) or mono-methylated (H3K9me1). Increased levels of H3 histone methylation at lysin-9 (H3K9) is related to tumor suppressor gene silencing. <i>JMJD1A</i> gene target Adrenomeduline (ADM) has shown to promote cell growth and tumorigenesis. JMJD1A and ADM expression, as well as H3K9 methylation level have been related with development risk and prognosis of several tumor types.</p><p>Methods and results</p><p>We aimed to evaluate JMJD1A, ADM, H3K9me1 and H3K9me2expression in paraffin-embedded tissue microarrays from 84 oral and oropharyngeal squamous cell carcinoma samples through immunohistochemistry analysis. Our results showed that nuclear JMJD1A expression was related to lymph node metastasis risk. In addition, JMJD1A cytoplasmic expression was an independent risk marker for advanced tumor stages. H3K9me1 cytoplasmic expression was associated with reduced disease-specific death risk. Furthermore, high H3K9me2 nuclear expression was associated with worse specific-disease and disease-free survival. Finally, high ADM cytoplasmic expression was an independent marker of lymph node metastasis risk.</p><p>Conclusion</p><p>JMJD1A, H3K9me1/2 and ADM expression may be predictor markers of progression and prognosis in oral and oropharynx cancer patients, as well as putative therapeutic targets.</p></div

Multivariate analysis of the relationship between disease relapse and disease specific survival and H3k9me2 expression and tumor size.

<p>Multivariate analysis of the relationship between disease relapse and disease specific survival and H3k9me2 expression and tumor size.</p

Multivariate analysis of the relationship between lymph node status and JMJD1A and ADM expression.

<p>Multivariate analysis of the relationship between lymph node status and JMJD1A and ADM expression.</p

Survival plots and immunohistochemistry.

<p><b>(A)</b> Negative H3K9me2 nuclear expression <b>(B)</b> Low H3K9me2 nuclear expression. <b>(C)</b> High H3K9me2 nuclear expression. (<b>D</b>) Disease relapse survival according to H3K9me2 nuclear expression. <b>(E)</b> Disease specific survival according to H3K9me2 nuclear expression. The scale bar indicates 10μμM. Magnification was 400x.</p

Epidemiological and prognostic features.

<p>Epidemiological and prognostic features.</p

Immunohistochemistry.

<p><b>(A)</b> Negative ADM cytoplasmic expression <b>(B)</b> Low ADM cytoplasmic expression. <b>(D)</b> High ADM cytoplasmic expression. The scale bar indicates 10μμM. Magnification was 400x.</p

Clinical and pathological tumor features and their association with H3K9me1 expression, according to cell localization.

<p>Clinical and pathological tumor features and their association with H3K9me1 expression, according to cell localization.</p

Influence of JMJD1A, H3K9me1, H3K9me2 and ADM in clinicopathological tumor features and patient survival in HNC.

<p>Nuclear JMJD1A expression increases lymph node positivity risk. In contrast, cytoplasmic expression decreases advanced tumor stage risk. Positive cytoplasmic H3K9me1 protein expression reduces disease specific death. High nuclear H3K9me2 expression causes a worse diseas-specific and disease-free survival. High cytoplasmic ADM expression is related with high lymph node metastasis risk.</p