Distinct histone H3 modification profiles correlate with aggressive characteristics of salivary gland neoplasms

Abstract

Post-translational modification of histones is the crucial event that affect many tumor-specific traits. A diverse type of histone modifications had been reported in different cancers with prognostic implications. This study aimed to examine the degree of histone H3 modifications in salivary gland neoplasms and their associations with tumor pathologic characteristics and proliferative activity. The expression of H3K9Ac, H3K18Ac, H3K9Me3 and Ki-67 in 70 specimens of salivary gland neoplasms, consisting of 30 mucoepidermoid carcinoma (MEC), 20 adenoid cystic carcinoma (ACC) and 20 pleomorphic adenoma (PA), were investigated immunohistochemically. The immunohistochemical scoring of 3 histone modification types and Ki-67 labeling index were determined. Overall, MEC demonstrated elevated H3K9Ac level compared with benign PA. Increased H3K9Me3 in MEC was positively correlated with small nest invasion at tumor front, advanced pathologic grade, and elevated proliferative index. In addition, the significant upregulation of all 3 types of histone H3 modification was noted in solid subtype of ACC and associated with increased cell proliferation. This study indicates that salivary gland neoplasms differentially acquire distinct patterns of histone H3 modification, which impact prognostically relevant cancer phenotypes. The hyperacetylation and methylation of histone H3 could be underpinning the prognostically worsen solid type of ACC, and the trimethylation of H3K9 may be involved in aggressive characteristics of MEC.

Enhanced Transcriptional Signature and Expression of Histone-Modifying Enzymes in Salivary Gland Tumors

“…Following this observation, we also investigated the levels of the repressive mark H3K9me3 mediated by SUV39H1 in tissues and detected elevated expression in PAC and ACCs compared to PA, indicating a potential functional role of SUV39H1 in these tumors that is mediated through the increased H3K9me3 levels. In agreement, Lam-Ubol and colleagues have shown increased H3K9me3 expression in MECs and ACCs that was correlated with the proliferative and aggressive phenotype of tumors [24]. Moreover, upregulation of the H3K9me3 protein mark in primary ACCs was associated with poor prognosis and distant metastasis, serving as a potent prognostic biomarker.…”

Role of Histone Deacetylases in the Pathogenesis of Salivary Gland Tumors and Therapeutic Targeting Options

“…Additionally, an inversely proportional relationship has been detected between H3 (lys9) acetylation and SGTs’ cell proliferation [ 69 ]. The methylation and hyperacetylation of H3 is linked to the aggressive phenotype of AdCC [ 64 , 70 , 71 ], and H3K9 trimethylation co-exists with high grade and invasive features of MECs. In both MECs and AdCCs, higher rates of histone H3 modifications are linked to higher cancer proliferation [ 71 ].…”

“…The methylation and hyperacetylation of H3 is linked to the aggressive phenotype of AdCC [ 64 , 70 , 71 ], and H3K9 trimethylation co-exists with high grade and invasive features of MECs. In both MECs and AdCCs, higher rates of histone H3 modifications are linked to higher cancer proliferation [ 71 ]. Particularly, the upregulation of H3K9Ac, H3K18Ac, and H3K9me3 in AdCC and upregulation of H3K9me3 in MECs were linked with increased Ki-67 expression and malignant pathological features, including aggressiveness [ 71 ].…”

“…In both MECs and AdCCs, higher rates of histone H3 modifications are linked to higher cancer proliferation [ 71 ]. Particularly, the upregulation of H3K9Ac, H3K18Ac, and H3K9me3 in AdCC and upregulation of H3K9me3 in MECs were linked with increased Ki-67 expression and malignant pathological features, including aggressiveness [ 71 ]. This event is attributed to H3K9me3 and H3K9Ac due to their interaction with genes that are involved in cell proliferation ( p21 Cip1 /Notch1/ERK ) [ 72 , 73 , 74 ].…”

Histopathological Aspects of The Prognostic Factors for Salivary Gland Cancers

“…In addition, though rare, the following tumors have specific proteins or gene alterations involving tumorigenesis: (i) nuclear protein in testis (NUT); NUT carcinoma, (ii) subfamily of ATPdependent chromatin remodeling complexes SWI/SNF (switch/sucrose non-fermentable); SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily B, member 1 (SMARCB1)-deficient high-grade transformed/dedifferentiated acinic cell carcinoma, (iii) BRAF; IPMN, (iv) neuroendocrine granules; small cell neuroendocrine carcinoma "Merkel type" (SNECM), large cell neuroendocrine carcinoma, and (v) salivary gland carcinoma with viral infection (human papillomavirus, EBV, polyomaviruses, and so on) [138][139][140][141][142][143][144][145][146][147][148][149]. These unique proteins or gene alterations might be related www.videleaf.com to tumorigenesis and, thus, may represent novel therapeutic targets.…”