Abstract
Simple SummaryHeterochromatin protein 1 is a histone code reader protein that recognizes histone H3 lysine 9 methylation. It acts as a transcriptional corepressor by forming heterochromatin. Since its discovery, the crucial roles of heterochromatin protein 1 in tumorigenesis have been constantly reported. Indeed, numerous studies report on the altered expression level of heterochromatin protein 1 in various cancers. The changed expression pattern of heterochromatin protein 1 is associated with tumorigenesis as it regulates diverse mechanisms such as heterochromatin formation, transcriptional regulation, DNA repair, cell cycle, and telomere maintenance. Despite the studies suggesting its role in tumorigenesis, the precise tumorigenic mechanism of heterochromatin protein 1 in each cancer type is still not established. In the present review, we summarize the studies conducted on the relationship between heterochromatin protein 1 and cancer. Also, we highlight the possibility of utilizing heterochromatin protein 1 as a prognostic marker and a therapeutic target of cancer.Dysregulation of epigenetic mechanisms as well as genomic mutations contribute to the initiation and progression of cancer. In addition to histone code writers, including histone lysine methyltransferase (KMT), and histone code erasers, including histone lysine demethylase (KDM), histone code reader proteins such as HP1 are associated with abnormal chromatin regulation in human diseases. Heterochromatin protein 1 (HP1) recognizes histone H3 lysine 9 methylation and broadly affects chromatin biology, such as heterochromatin formation and maintenance, transcriptional regulation, DNA repair, chromatin remodeling, and chromosomal segregation. Molecular functions of HP1 proteins have been extensively studied, although their exact roles in diseases require further study. Here, we comprehensively review the studies that have revealed the altered expression of HP1 and its functions in tumorigenesis. In particular, the distinctive effects of each HP1 subtype, namely HP1α, HP1β, and HP1γ, have been thoroughly explored in various cancer types. We also highlight how HP1 can serve as a potential biomarker for cancer prognosis and therapeutic target for cancer patients.
Highlights
Heterochromatin protein 1 (HP1) was first found in Drosophila melanogaster as a nonhistone chromosomal protein that affects gene silencing via heterochromatin formation and structure maintenance [1]
The molecular function of HP1 protein has been studied for a long time, and today many researchers have much interest in the physiological significance of HP1, which can be further associated with the disease phenotype
Recent papers observing the relationship between HP1 and tumorigenesis have implied that HP1 is deeply associated with tumorigenesis via modulating diverse molecular mechanisms such as cell cycle, DNA repair, and transcriptional regulation [18]
Summary
Heterochromatin protein 1 (HP1) was first found in Drosophila melanogaster as a nonhistone chromosomal protein that affects gene silencing via heterochromatin formation and structure maintenance [1]. In addition to its involvement in heterochromatin formation, HP1 is known for its role in cellular processes, including transcriptional regulation, DNA damage response (DDR), cell cycle, centromere and telomere maintenance, and splicing. HP1α is recruited to the DNA damage site by p150CAF-1 and promotes homologous recombination (HR) repair by recruiting HR components such as breast cancer type 1 (BRCA1), TP53-binding protein 1 (53BP1), and RAD5. LBH589 reactivates ER expression by removing repressive chromatin marks and disturbing the interaction of HP1α with ER promoters in ER-negative breast cancer, preventing the formation of heterochromatin. The overexpression of YY1 in HS578T cells downregulates cell migration independent of HP1α These results show that YY1 positively regulates HP1α by binding to the HP1α gene promoter in non-invasive breast cancer cells but not in invasive breast cancer cells. HP1β depletion in breast cancer cells largely increases the sensitivity to poly(ADP-ribose)polymerase (PARP) inhibitor, which suppresses DNA repair. The capability of HP1γ to regulate rRNA transcription could be possibly utilized for the treatment of TNBC
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