Silencing the genome: role of HUSH complex in retrotransposon regulation and cancer development

Retrotransposons comprise approximately 42% of the human genome and contribute to genomic diversity. Their improper regulation leads to genomic instability and, potentially, cancer. The Human Silencing Hub (HUSH) complex plays a significant role in silencing the genome via epigenetic regulation, specifically through H3K9me3 deposition. Its current identified function is to maintain the genomic stability; however, there is still ambiguity and further study is required about the exact mechanism by which the HUSH complex controls the retrotransposon activity and how its dysfunction contributes to cancer. This systematic review examines genome-wide transcriptional and epigenetic studies whose focus is the role of the HUSH complex in the silencing of retrotransposons and its consequences in cancer. The study also aims to clarify how HUSH complex dysregulation affects gene expression patterns and contributes to tumorigenesis. A comprehensive literature search was conducted through PubMed, ScienceDirect, ProQuest, and Lilac databases, yielding 693 articles. After implementing predefined inclusion and exclusion criteria, 6 studies were selected for analysis. The data extraction from precisely included studies focused on HUSH complex relations with retrotransposons and its effect on cancer-related genes. The study highlights the significant role of the HUSH complex, which efficiently silences retrotransposons like LINE-1 and ERVs, especially by H3K9me3 deposition. Through immune evasion, DNA damage, and retrotransposon reactivation, dysregulation of HUSH components, SETDB1 and MPP8, has been associated with the advancement of cancer. MPP8 knockdown caused differentiation in Acute Myeloid Leukemia (AML), but SETDB1 deletion increased tumor immunogenicity in melanoma. Conclusively, HUSH complex is a key epigenetic regulator of retrotransposons, and its dysfunction contributes to cancer pathogenesis. HUSH components (e.g., SETDB1, MPP8) present, as potential therapeutic and diagnostic biomarkers for different cancers.