miR-217 regulates normal and tumor cell fate following induction of Endoplasmic Reticulum Stress.

Rapidly proliferating cancer cells must thrive in a microenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limiting as tumor volume expands beyond the established vascularity of the tissue. Limits in nutrient availability typically trigger growth arrest and/or apoptosis to prevent cellular expansion. However, tumor cells frequently co-opt cellular survival pathways thereby favoring cell survival under this environmental stress. The Unfolded Protein Response (UPR) pathway is typically engaged by tumor cells to favor adaptation to stress. PERK, an endoplasmic reticulum (ER) protein kinase and UPR effector is activated in tumor cells and contributes tumor cell adaptation by limiting protein translation and balancing redox stress. PERK also induces micro-RNAs that contribute to tumor adaptation. miR-211 and miR-216b were previously identified as a PERK-ATF4 regulated micro-RNAs that regulate cell survival. We have identified another PERK responsive miRNA, miR-217, with increased expression under prolonged ER stress. Key targets of miR-217 are identified as TRPM1, the host gene for miR-211 and EZH2. Evidence is provided that miR-217 expression is essential for the rapid loss of miR-211 in prolonged ER stress and provides a functional link for determining whether cells adapt to stress or commit to apoptosis. Implications: PERK-dependent induction of miR-217 limits accumulation and function of the pro-survival micro-RNA, miR-211, to establish cell fate and promote cell commitment to apoptosis.