Nuclear Pore Protein NUP210 Depletion Suppresses Metastasis Through Heterochromatin-mediated Disruption of Tumor Cell Mechanical Response

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Dec 14

PMID 34903738

Citations 21

Authors

Ruhul Amin

Anjali Shukla

Jacqueline Jufen Zhu

Sohyoung Kim

Ping Wang

Simon Zhongyuan Tian

Andy D Tran

Debasish Paul

Steven D Cappell

Sandra Burkett

Huaitian Liu

Maxwell P Lee

Michael J Kruhlak

Jennifer E Dwyer

R Mark Simpson

Gordon L Hager

Yijun Ruan

Kent W Hunter

Affiliations

Soon will be listed here.

Abstract

Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression. Here, we identify nucleoporin NUP210 as a metastasis susceptibility gene for human estrogen receptor positive (ER+) breast cancer and a cellular mechanosensor. Nup210 depletion suppresses lung metastasis in mouse models of breast cancer. Mechanistically, NUP210 interacts with LINC complex protein SUN2 which connects the nucleus to the cytoskeleton. In addition, the NUP210/SUN2 complex interacts with chromatin via the short isoform of BRD4 and histone H3.1/H3.2 at the nuclear periphery. In Nup210 knockout cells, mechanosensitive genes accumulate H3K27me3 heterochromatin modification, mediated by the polycomb repressive complex 2 and differentially reposition within the nucleus. Transcriptional repression in Nup210 knockout cells results in defective mechanotransduction and focal adhesion necessary for their metastatic capacity. Our study provides an important role of nuclear pore protein in cellular mechanosensation and metastasis.

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