Postdoc Neekkan Dey has work accepted into Molecular Cancer Research Journal

Neekkan Dey, a postdoc in J. Alan Diehl’s group in the Department of Biochemistry at Case Comprehensive Cancer Center, had work accepted for publication in the Molecular Cancer Research Journal by the American Association of Cancer Research.

The study, “miR-217 regulates normal and tumor cell fate following induction of Endoplasmic Reticulum Stress,” unveils the intricate interplay of PERK-responsive microRNAs (miRNAs), miR-211 and miR-217, in deciding cell fate during acute ER stress.

The PERK arm of the Unfolded Protein Response (UPR) is highlighted as a significant pathway through which miRNA regulation impacts cell fate under stress. Previous research from the group identified PERK-induced miR-211, as a prosurvival miRNA preventing premature chop accumulation and promoting stress resolution. However, the transient nature of miR-211 accumulation, coinciding with increased cell death, creates a knowledge gap in understanding cell commitment to stress resolution versus cell death. The current study introduces miR-217, which shows increased expression during prolonged ER stress when miR-211 is suppressed. The induction of miR-217 involves a pathway primarily composed of PERK, ATF4, and CHOP. MiR-217 directly targets the 3′ untranslated region (UTR) of Trpm1, which contains miR-211 in its intronic sequence. Gene expression assays demonstrate that the kinetics of miR-217-induced regulation of Trpm1 expression mirror those of pri-211, pre-211, and mature miR-211. The findings shed light on a novel mechanism responsible for decreased miR-211 stability following prolonged ER stress.

Additionally, miR-217 is revealed to target key components of the PRC2 complex, including the Ezh2 methyltransferase and SUZ12, leading to increased expression levels of ATF4 and CHOP. This sensitizes cells to ER stress-dependent apoptosis under prolonged ER stress conditions. In summary, the study provides valuable insights into the molecular mechanisms by which PERK-induced miRNAs, particularly miR-211 and miR-217, coordinate cell fate in response to proteotoxic activation of the UPR during acute ER stress.

View the article.