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

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. Med4 downregulation effectively awakened dormant breast cancer cells, prompting macroscopic metastatic outgrowth in the lungs. Med4 depletion 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 by Med4 depletion. MED4 gene deletions were observed in patients with metastatic breast cancer, and reduced MED4 expression correlates with worse prognosis, highlighting its significance as a potential biomarker for recurrence.