Noncanonical Activity of Med4 as a Gatekeeper of Metastasis through Epigenetic Control of Integrin Signaling

Abstract

Breast cancer metastatic relapse after a latency period, known as metastatic dormancy. Through genetic screening in mice, we identified the mediator complex subunit 4 (Med4) as a novel tumor-cell intrinsic gatekeeper in metastatic reactivation.Med4downregulation effectively awakened dormant breast cancer cells, prompting macroscopic metastatic outgrowth in the lungs.Med4depletion results in profound changes in nuclear size and three-dimensional chromatin architecture from compacted to relaxed states in contrast to the canonical function of the Mediator complex. These changes rewire the expression of extracellular matrix proteins, integrins, and signaling components resulting in integrin-mediated mechano-transduction and activation of YAP and MRTF. The assembly of stress fibers pulls on the nuclear membrane and contributes to reinforcing the overall chromatin modifications byMed4depletion. MED4 gene deletions were observed in patients with metastatic breast cancer, and reducedMED4expression correlates with worse prognosis, highlighting its significance as a potential biomarker for recurrence.Significance: This work establishes the first link between Med4 and its role as an epigenetic and transcriptional repressor of ECM programs that reactivates dormant tumor cells in breast cancer metastasis. We highlight the distinct noncanonical role of Med4, in contrast to Med1, as well as the functional implicationsin vitroandin vivo. We have functionally validated the aberrant signaling pathways activated through both genetic add back and chemical inhibition and correlate our findings with Med4 expression, metastatic potential, and overall outcome in retrospective patient cohorts.