# Compressive stress–driven Piezo1 activation and Rho-ROCK mechanotransduction promote tumor progression via epigenetic mechanical memory

## TL;DR

Tumors use mechanical forces to activate Piezo1 and Rho-ROCK signaling, leading to epigenetic changes that promote cancer growth.

## Contribution

The study identifies Piezo1 as a mechanosensor linking compressive stress to tumor progression via epigenetic memory.

## Key findings

- Compressive stress activates Piezo1 and Rho-ROCK signaling to promote tumor growth in vivo.
- Piezo1 silencing abolishes compression-induced Rho-ROCK activation and tumor progression.
- Compressive stress induces histone modifications linked to open chromatin and cancer gene regulation.

## Abstract

Rapidly growing tumors experience high tissue-level forces, particularly when growing within a restricted space. These require counteracting by intracellular forces to prevent tissue damage. Here, we reveal the ion channel Piezo1 as a mechanosensor of compressive force, activating Rho–Rho kinase (ROCK) mechanotransduction to generate intracellular forces and enhancing malignant characteristics of tumors. Compressive stress promoted cancer growth in vivo in a Rho-ROCK–dependent manner. Silencing Piezo1 abolished compression-induced Rho-ROCK activation and tumor progression in this model. Accordingly, elevated PIEZO1 is associated with 35% poorer survival of patients with breast cancer. We show that acute compressive forces engender epigenetic mechanical memory via Piezo1-activated Rho-ROCK signaling, promoting tumor growth in vivo. Compressive stress promoted ROCK-dependent histone modifications associated with open chromatin, including acetylation of key histone 3–lysine residues, regulating the expression of cancer-related genes across cell, explant, and in vivo tumor models. Our observations suggest that the PIEZO1-RHO-ROCK axis links tissue-level forces to persistent tumor-promoting epigenetic changes and merits evaluation as a mechanotherapy target in cancer.

Compressive force drives PIEZO1-RHO-ROCK mechanotransduction and establishes an epigenetic memory that promotes tumor progression.