KRT13 promotes stemness and drives metastasis in breast cancer through a plakoglobin/c-Myc signaling pathway

Lijuan Yin,Gina Chia-Yi Chu,Stefan Mrdenovic,Qinlong Li,Haiyen E Zhau,Michael S Lewis,Gangning Liang,Peng Duan,Leland W K Chung,Jayoung Kim,Sungyong You,Hong Bu,Ruoxiang Wang,Boyang Jason Wu

doi:10.1186/s13058-022-01502-6

Abstract

BackgroundKeratins (KRTs) are intermediate filament proteins that interact with multiple regulatory proteins to initiate signaling cascades. Keratin 13 (KRT13) plays an important role in breast cancer progression and metastasis. The objective of this study is to elucidate the mechanism by which KRT13 promotes breast cancer growth and metastasis.MethodsThe function and mechanisms of KRT13 in breast cancer progression and metastasis were assessed by overexpression and knockdown followed by examination of altered behaviors in breast cancer cells and in xenograft tumor formation in mouse mammary fat pad. Human breast cancer specimens were examined by immunohistochemistry and multiplexed quantum dot labeling analysis to correlate KRT13 expression to breast cancer progression and metastasis.ResultsKRT13-overexpressing MCF7 cells displayed increased proliferation, invasion, migration and in vivo tumor growth and metastasis to bone and lung. Conversely, KRT13 knockdown inhibited the aggressive behaviors of HCC1954 cells. At the molecular level, KRT13 directly interacted with plakoglobin (PG, γ-catenin) to form complexes with desmoplakin (DSP). This complex interfered with PG expression and nuclear translocation and abrogated PG-mediated suppression of c-Myc expression, while the KRT13/PG/c-Myc signaling pathway increased epithelial to mesenchymal transition and stem cell-like phenotype. KRT13 expression in 58 human breast cancer tissues was up-regulated especially at the invasive front and in metastatic specimens (12/18) (p < 0.05). KRT13 up-regulation in primary breast cancer was associated with decreased overall patient survival.ConclusionsThis study reveals that KRT13 promotes breast cancer cell growth and metastasis via a plakoglobin/c-Myc pathway. Our findings reveal a potential novel pathway for therapeutic targeting of breast cancer progression and metastasis.

Highlights

Keratins (KRTs) are intermediate filament proteins that interact with multiple regulatory proteins to initiate signaling cascades
We explored the mechanism by which Keratin 13 (KRT13) promotes breast cancer progression and metastasis
KRT13 overexpression increases breast cancer proliferation, migration and invasion in vitro, and promotes tumorigenesis and metastasis in vivo We previously reported that KRT13 induced prostate cancer progression and metastasis [18]

Summary

Introduction

Keratins (KRTs) are intermediate filament proteins that interact with multiple regulatory proteins to initiate signaling cascades. Breast cancer is the leading cause of cancer-related death among women worldwide. It is a heterogeneous disease with divergent molecular alterations and cellular changes. Keratins (KRTs) are considered structural proteins ranging in sizes from 40 to 76 kDa. Keratins (KRTs) are considered structural proteins ranging in sizes from 40 to 76 kDa They are the major component of intermediate filaments (IFs) in the intracytoplasmic cytoskeleton of epithelial and endothelial cells. Recent studies suggest that KRTs in cancer cells are epithelial marker proteins but are mediators capable of interacting with a range of proteins to regulate signaling networks associated with cell death, survival, proliferation, migration, invasion and metastasis [1,2,3]

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