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Dynamic assembly of chromatin complexes during cellular senescence: implications for the growth arrest of human melanocytic nevi.

ABSTRACT: The retinoblastoma (RB)/p16(INK4a) pathway regulates senescence of human melanocytes in culture and oncogene-induced senescence of melanocytic nevi in vivo. This senescence response is likely due to chromatin modifications because RB complexes from senescent melanocytes contain increased levels of histone deacetylase (HDAC) activity and tethered HDAC1. Here we show that HDAC1 is prominently detected in p16(INK4a)-positive, senescent intradermal melanocytic nevi but not in proliferating, recurrent nevus cells that localize to the epidermal/dermal junction. To assess the role of HDAC1 in the senescence of melanocytes and nevi, we used tetracycline-based inducible expression systems in cultured melanocytic cells. We found that HDAC1 drives a sequential and cooperative activity of chromatin remodeling effectors, including transient recruitment of Brahma (Brm1) into RB/HDAC1 mega-complexes, formation of heterochromatin protein 1 beta (HP1 beta)/SUV39H1 foci, methylation of H3-K9, stable association of RB with chromatin and significant global heterochromatinization. These chromatin changes coincide with expression of typical markers of senescence, including the senescent-associated beta-galactosidase marker. Notably, formation of RB/HP1 beta foci and early tethering of RB to chromatin depends on intact Brm1 ATPase activity. As cells reached senescence, ejection of Brm1 from chromatin coincided with its dissociation from HP1 beta/RB and relocalization to protein complexes of lower molecular weight. These results provide new insights into the role of the RB pathway in regulating cellular senescence and implicate HDAC1 as a likely mediator of early chromatin remodeling events.

SUBMITTER: Bandyopadhyay D

PROVIDER: S-EPMC1974778 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose: Melanocytic nevi are common cutaneous lesions. This study aimed to demonstrate the concordance and discordance between clinical and histopathological diagnoses of melanocytic nevi and the importance of histological evaluation in differentiating malignant lesions from diseases with similar clinical manifestations. Patients and Methods: We studied 4,561 consecutive patients with a clinical diagnosis of melanocytic nevi from 2014 to 2019. We compared the clinical diagnosis with the histopathological diagnosis to establish a histopathological concordance rate and then investigated the effects of clinical characteristics and the reasons for removal on misclassification. Results: Among 4,561 patients who were clinically diagnosed with melanocytic nevi, the overall histopathological concordance rate was 82.11% (3,745 of 4,561 patients), while the histopathological discordance rate was 17.89% (816 of 4,561 patients). The histopathological concordance included 90.25% common acquired melanocytic nevi (3,380 of 3,745 patients) and 9.75% other benign melanocytic neoplasms (365 of 3,745 patients). The most common diagnostic change was to seborrheic keratosis (n = 470, 10.30%), followed by basal cell carcinoma (n = 64, 1.40%), vascular tumor (n = 53, 1.16%), fibroma (n = 43, 0.94%), epidermoid cyst (n = 34, 0.75%), wart (n = 30, 0.66%), melanoma (n = 24, 0.53%), Bowen's disease (n = 16, 0.35%), squamous cell carcinoma (n = 4, 0.09%), keratoacanthoma (n = 2, 0.04%), and other neoplasms (n = 76, 1.67%). Male sex, old age, location of the lesion, and the reasons for removal have a potential effect on misclassification. The percentages of misclassified lesions on the trunk and limbs and the perineum and buttocks were higher than those in lesions without a change in diagnosis. Importantly, locations of lesions on the head and neck were significantly related to a change in diagnosis to non-melanoma skin cancer, while locations on the hands and feet were significantly related to a change in diagnosis to melanoma. In addition to a typical clinical features, removal due to lesion changes or repeated stimulation was significantly associated with a change in diagnosis to melanoma. Conclusions: Our study emphasizes the clinical differential diagnosis of melanocytic nevi, especially the possibility of malignant tumors. The occurrence of clinical features associated with clinicopathological discordance should raise the clinical suspect and be carefully differentiated from malignant tumors.

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Dynamic assembly of chromatin complexes during cellular senescence: implications for the growth arrest of human melanocytic nevi.

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