Aging-dependent dysregulation of EXOSC2 is maintained in cancer as a dependency
Reprogramming of aged donor tissue cells into induced pluripotent stem cells (A-iPSC) preserved the epigenetic memory of original aged-donor tissue, defined as genomic instability and poor tissue differentiation in our previous study. The unbalanced expression of RNA exosome subunits affects the RNA degradation complex function and is associated to geriatric diseases including premature aging and cancer progression. Here, we hypothesized that the aging-dependent progressive subtle dysregulation of EXOSC2 (exosome component 2) causes the aging-traits (abnormal cell cycle & division and poor tissue differentiation). We used the embryonic stem cells  as a unique tool to study EXOSC2 function as the aging-trait epigenetic memory determined in A-iPSC because these aging-traits could not be studied in senesced aged cells or immortalized cancer cells. We found that the regulatory subunit of PP2A phosphatase, PPP2R5E, is a key target of the EXOSC2 and controls the microtubule polymerization. We also validated these aging-traits as a dependency in a mouse model of colon carcinogenesis. Overall design: Comparative gene expression profiling analysis of RNA-seq data for ESC cells and its KD derivatives (shEXOSC2).