SEED-MEDIATED RNA INTERFERENCE OF ANDROGEN SIGNALING AND SURVIVAL NETWORKS INDUCES CELL DEATH IN PROSTATE CANCER CELLS

Abstract

Resistance to anti-androgen therapy in prostate cancer (PCa) is often driven by genetic and epigenetic aberrations in the androgen receptor (AR) and coregulators that maintain androgen signaling activity. We show that specific small RNAs downregulate expression of multiple essential and AR-coregulatory genes, leading to potent androgen signaling inhibition and PCa cell death. Expression of different sh-/siRNAs designed to target TMEFF2, preferentially reduce viability of PCa, but not benign, cells and growth of murine xenografts. Surprisingly this effect is independent of TMEFF2 expression. Transcriptomic and sh/siRNA seed sequence studies indicate that expression of these toxic shRNAs lead to downregulation of AR-coregulatory and essential genes thru mRNA 3-UTR sequence complementarity to the seed sequence of the toxic shRNAs. These findings reveal a specialized form of the Death Induced by Survival gene Elimination (DISE) mechanism in PCa cells, that we have termed Androgen Network (AN)-DISE, and suggest a novel therapeutic strategy for PCa.