Transcriptome Analysis of Human Cancer Cells with Depleted or Overexpressed STELLA Proteins [RNA-seq]

UHRF1 maintains DNA methylation by recruiting DNA methyltransferases (DNMT’s) to chromatin. These dynamics are well defined for mouse STELLA (mSTELLA) but poorly characterized for human STELLA (hSTELLA). Herein, we demonstrate that hSTELLA is defective, while mSTELLA is fully proficient in associating with UHRF1 and inhibiting the abnormal DNA methylation and oncogenic functions of UHRF1 in human cancer cells. We illustrate, in structural studies a region of low sequence homology between the above STELLA orthologs, allows mSTELLA but not hSTELLA to bind tightly to the essential histone binding domains of UHRF1, thus mediating their above functional differences. The ortholog-specific binding modes of STELLA proteins with UHRF1 prompt us to explore a rationale for designing UHRF1 inhibitors for cancer therapy. For this, we use a lipid nanoparticle (LNP)-mediated mRNA delivery approach demonstrating the short mSTELLA, but not hSTELLA regions are required to reverse cancer-specific DNA methylation abnormalities and impair CRC tumor growth.