Chemotherapy-induced S100A10 recruits KDM6A to facilitate OCT4-mediated breast cancer stemness
Haiquan Lu, … , Yueyang J. Wang, Gregg L. Semenza
Haiquan Lu, … , Yueyang J. Wang, Gregg L. Semenza
Published May 19, 2020
Citation Information: J Clin Invest. 2020;130(9):4607-4623. https://doi.org/10.1172/JCI138577.
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Research Article Oncology

Chemotherapy-induced S100A10 recruits KDM6A to facilitate OCT4-mediated breast cancer stemness

Abstract

Breast cancer stem cells (BCSCs) play a critical role in cancer recurrence and metastasis. Chemotherapy induces BCSC specification through increased expression of pluripotency factors, but how their expression is regulated is not fully understood. Here, we delineate a pathway controlled by hypoxia-inducible factor 1 (HIF-1) that epigenetically activates pluripotency factor gene transcription in response to chemotherapy. Paclitaxel induces HIF-1–dependent expression of S100A10, which forms a complex with ANXA2 that interacts with histone chaperone SPT6 and histone demethylase KDM6A. S100A10, ANXA2, SPT6, and KDM6A are recruited to OCT4 binding sites and KDM6A erases H3K27me3 chromatin marks, facilitating transcription of genes encoding the pluripotency factors NANOG, SOX2, and KLF4, which along with OCT4 are responsible for BCSC specification. Silencing of S100A10, ANXA2, SPT6, or KDM6A expression blocks chemotherapy-induced enrichment of BCSCs, impairs tumor initiation, and increases time to tumor recurrence after chemotherapy is discontinued. Pharmacological inhibition of KDM6A also impairs chemotherapy-induced BCSC enrichment. These results suggest that targeting HIF-1/S100A10–dependent and KDM6A-mediated epigenetic activation of pluripotency factor gene expression in combination with chemotherapy may block BCSC enrichment and improve clinical outcome.

Authors

Haiquan Lu, Yangyiran Xie, Linh Tran, Jie Lan, Yongkang Yang, Naveena L. Murugan, Ru Wang, Yueyang J. Wang, Gregg L. Semenza

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Figure 16

S100A10 is associated with poor clinical outcome in breast cancer patients.

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S100A10 is associated with poor clinical outcome in breast cancer patien...
(A) S100A10 mRNA levels in normal breast tissue (n = 111), invasive ductal breast carcinoma (BC) (n = 641), and invasive lobular BC (n = 71) were accessed from TCGA database and compared; ***P < 0.001 vs. normal (1-way ANOVA with Bonferroni’s post hoc test). (B) Kaplan-Meier analyses of relapse-free survival were performed based on clinical and molecular data from 3,951 breast cancer patients (cohort: All, left) or from a subgroup of 798 breast cancer patients who received chemotherapy (right). The patients were stratified by S100A10 mRNA levels in the primary tumor, which were greater (red) or less (black) than the median level. The hazard ratio (HR) and P value (log-rank test) are shown. (C) Levels of S100A10 mRNA and a BCSC signature composed of transcripts of 20 genes in primary breast cancer samples were accessed from TCGA database, and the correlation was analyzed by Pearson’s test. (D and E) Clinical and molecular data from 3 data sets were accessed from GEO. S100A10 mRNA levels in the primary breast cancer from patients who had recurrence (D) or metastasis (E) at year 1, 3, or 5 was compared with patients who had no recurrence or metastasis at the same time point; *P < 0.05, **P < 0.01 (Student’s t test).