MYSM1 suppresses cervical cancer progression by triggering ITPR1-mediated autophagy

Myb-like, SWIRM and MPN domains 1 (MYSM1), a histone H2A deubiquitinase (2A-DUB), is essential for hematopoietic development and immune regulation, and has recently been found to be involved in modulation of several tumors, including breast, colorectal, and prostate cancer. However, its role in cervical cancer (CC) pathogenesis remains unexplored. Based on public transcriptome datasets including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Human Protein Atlas (HPA), we profiled the pan-cancer expression landscape of MYSM1 and its clinical relevance in CC. Survival analysis was validated using the TCGA, GSE44001, and our internal 44-case clinical cohort. A series of in vitro and in vivo functional assays were performed to explore the regulatory effects of MYSM1 on CC malignant behaviors and autophagy. ChIP-Seq, transcriptomic profiling, and correlation analysis were applied to screen potential downstream target genes of MYSM1 , while functional enrichment analyses, e.g., Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA) and cellular rescue assays were conducted to verify the MYSM1-inositol 1,4,5-trisphosphate receptor type 1 (ITPR1)-autophagy regulatory axis. Mendelian randomization (MR) analysis was further performed using the GWAS Catalog datasets to evaluate the genetic association of MYSM1 and ITPR1 with CC susceptibility, combined with validation in paired clinical CC specimens. MYSM1 is aberrantly expressed across pan-cancer, and profoundly downregulated in CC tissues. High MYSM1 expression is positively correlated with benign clinicopathological characteristics of CC patients, consistent with its tumor-suppressive role. Functional experiments confirmed that MYSM1 restrains CC cell proliferation, migration, and invasion in vitro and in vivo, and significantly promotes cellular autophagy. Mechanistically, ITPR1 was identified as a key downstream gene epigenetically activated by MYSM1. ITPR1 functions as an autophagy inducer and is associated with favorable clinical phenotypes in CC, thereby mediating the anti-tumor effects of MYSM1, further forming a MYSM1-ITPR1-autophagy regulatory axis. Both MYSM1 and ITPR1 were downregulated in 44 paired CC tumor tissues, possessing diagnostic and prognostic potential for CC. MR analysis revealed a modest suggestive genetic association between genetically predicted MYSM1 and ITPR1 expression and CC susceptibility. MYSM1 is an autophagy promoter and can exert tumor-suppressive effects on CC primarily through epigenetic activation of ITPR1. Axis of MYSM1-ITPR1-autophagy shows diagnostic and prognostic implications, and may be developed as a potential therapeutic target for CC in clinic.