Heterochromatin protein 1α: a hallmark of cell proliferation relevant to clinical oncology

Abstract

Mammalian cells contain three closely related heterochromatin protein 1 (HP1) isoforms, HP1α, β and γ, which, by analogy to their unique counterpart in Schizosaccharomyces pombe, have been implicated in gene silencing, genome stability and chromosome segregation. However, the individual importance of each isoform during normal cell cycle and disease has remained an unresolved issue. Here, we reveal that HP1α shows a proliferation-dependent regulation, which neither HP1β nor γ display. During transient cell cycle exit, the HP1α mRNA and protein levels diminish. Transient depletion of HP1α, but not HP1β or γ, in tumoural and primary human cells leads to defects in chromosome segregation. Notably, analysis of an annotated collection of samples derived from carcinomas reveals an overexpression of HP1α mRNA and protein, which correlates with clinical data and disease outcome. Our results unveil a specific expression pattern for the HP1α isoform, suggesting a unique function related to cell division and tumour growth. The overexpression of HP1α constitutes a new example of a potential epigenetic contribution to tumourigenesis that is of clinical interest for cancer prognosis.

Functional characterization of ATAD2 as a new cancer/testis factor and a predictor of poor prognosis in breast and lung cancers

“…This conclusion is in line with and generalizes the previous observation that the overexpression of factors restricting chromatin dynamics such as HP1-a (De Koning et al, 2009) could highly stimulate oncogenesis.…”

Differential contribution of HP1 proteins to DNA end resection and homology-directed repair

“…The sequences of the siRNA duplexes used (MWG eurofins) were as follows: siLuciferase (control), CGU ACG CGG AAU ACU UCG A; 35 siHP1α, #1-CCT GAG AAA AAC TTG GAT T used in the majority of the experiments 36 and organisms could help to deepen our understanding of the mechanistic basis of such an opposite behavior of HP1 paralogs on HDR efficiency. In particular, it will be important to consider how the ability of HP1 paralogs to heterodimerize 7 might impact on their contribution to DNA repair.…”

“…We pre-sensitized the cells with 10 μg/ml viable Hoechst dye 33258 (Sigma-Aldrich) for 5 min at 37°C. We performed laser microirradiation using an inverted confocal microscope (LSM 510 Meta; Carl Zeiss, Inc.) equipped with a 37°C heating chamber and a 25-mW 405 nm #2-GGA ATG AAC ATG AGA CTT A; siHP1β, #1-AGG AAT ATG TGG TGG AAA A used in the majority of the experiments 36 and #2-AGG TAA GAC AGT AGG GAA A; siHP1γ, #1-AGG TCT TGA TCC TGA AAG A used in the majority of the experiments 36 and #2-GGT GAA CAG TGG TTA ATA A; siCtIP, GCU AAA ACA GGA ACG AAU C; 21 siKU80 (Dharmacon Smartpool); siBRCA2, AAC TGA GCA AGC CTC AGT CAA; 37 siRAD52, ACA CAT TAG CCT TGA ACA A.…”

Heterochromatin protein 1 expression is reduced in human thyroid malignancy

“…Although generally ubiquitous in normal tissue, differential expression of each HP1 isoform has been observed in both human tumor derived tissues and cells. [3][4][5][6][7][8][9] The pattern of expression for HP1 isoforms in solid tumors appears to vary with the tumor context. 3,5,7,9,10 Loss of HP1b expression has been reported in poorly differentiated colon cancers, invasive melanoma lesions, and prostate cancer.…”

“…[3][4][5][6][7][8][9] The pattern of expression for HP1 isoforms in solid tumors appears to vary with the tumor context. 3,5,7,9,10 Loss of HP1b expression has been reported in poorly differentiated colon cancers, invasive melanoma lesions, and prostate cancer. [11][12][13] Loss of HP1a expression has been observed in metastatic lesions, 5 and in medulloblastomas and advanced papillary thyroid carcinomas with poor outcome.…”