MECOM: A novel player in AR-driven Treatment Resistant Castration-Resistant Prostate Cancer

ABSTRACT: Reprogramming of the androgen receptor (AR) cistrome is associated with disease progression, and advanced castrate-resistant prostate cancers (CRPC) tend to rely on a reprogrammed/non-canonical AR signaling that is addictive to AR signaling inhibitor (ARSI) resistance. We identified EVI1, an oncogenic nuclear transcription factor, EVI1 coded by MECOM, as a novel AR-recruited co-activator for non-canonical signaling. In prostate cancer, MECOM is exclusively overexpressed in CRPC and enzalutamide-resistant CRPC and interacts with AR in the nucleus. MECOM knockdown cells exhibited decreased proliferation, aberration of critical cell survival transcriptional programs, suppressed super-enhancer (SE) activity, and increased pro-apoptotic signatures. Intriguingly, MECOM overexpression is vulnerable to PARP inhibitors regardless of DDR or HRR gene mutation status. These insights uncover the mechanistic role of MECOM in AR reprogrammed cistrome for cell survival and its vulnerability. More importantly, this study suggests that MECOM overexpression may be another biomarker that could significantly broaden the use of PARP inhibitors beyond those with HRR gene mutations.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Prostate Adenocarcinoma

SUBMITTER: Remi Adelaiye-Ogala  

LAB HEAD: Remi adelaiye-Ogala

PROVIDER: PXD062331 | Pride | 2026-06-08

REPOSITORIES: Pride