Interaction of Nrf2 with dimeric STAT3 induces IL-23 expression: Implications for breast cancer progression

Su-Jung Kim; Soma Saeidi; Nam-Chul Cho; Seung Hyeon Kim; Han-Byoel Lee; Wonshik Han; Dong-Young Noh; Young-Joon Surh

doi:10.1016/j.canlet.2020.11.047

Interaction of Nrf2 with dimeric STAT3 induces IL-23 expression: Implications for breast cancer progression

Cancer Lett. 2021 Mar 1:500:147-160. doi: 10.1016/j.canlet.2020.11.047. Epub 2020 Dec 3.

Authors

Su-Jung Kim¹, Soma Saeidi², Nam-Chul Cho³, Seung Hyeon Kim⁴, Han-Byoel Lee⁵, Wonshik Han⁵, Dong-Young Noh⁵, Young-Joon Surh⁶

Affiliations

¹ Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.
² Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea.
³ Korea Chemical Bank, Korea Research Institute of Chemical Technology, Daejeon, 34114, South Korea.
⁴ Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Cancer Research Institute, Seoul National University, Seoul, 03080, South Korea.
⁵ Cancer Research Institute, Seoul National University, Seoul, 03080, South Korea; Department of Surgery, Seoul National University College of Medicine, Seoul, 03087, South Korea.
⁶ Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea; Cancer Research Institute, Seoul National University, Seoul, 03080, South Korea. Electronic address: surh@snu.ac.kr.

PMID: 33278500
DOI: 10.1016/j.canlet.2020.11.047

Abstract

Persistent activation of STAT3 and Nrf2 is considered to stimulate the aggressive behavior of basal-like breast cancer (BLBC). However, the precise mechanism underlying sustained overactivation of these transcription factors and their roles in breast cancer progression remain elusive. Analysis of the TCGA multi-omics data showed that high levels of STAT3 and Nrf2 mRNA were correlated with elevated expression of P-STAT3^Y705 and Nrf2 target proteins in breast cancer patients. Our present study demonstrates a unique interaction between Nrf2 and STAT3 in the maintenance and progression of BLBC. RNA sequencing analysis identified the gene encoding IL-23A upregulated by concurrent binding of STAT3 and Nrf2 to its promoter. IL-23A depletion also showed the similar phenotypic changes to those caused by double knockdown of both transcription factors. In conclusion, the STAT3-Nrf2 interaction accelerates BLBC growth and progression by augmenting IL-23A expression, which underscores the importance of subtype-specific molecular pathways in human breast cancer.

Keywords: Breast cancer; IL-23A; Nrf2; STAT3.

MeSH terms

Animals
Breast / metabolism
Breast / pathology
Breast Neoplasms / genetics*
Breast Neoplasms / pathology
Breast Neoplasms / therapy
Cell Line, Tumor
Disease Progression
Female
Gene Expression Regulation, Neoplastic / genetics
Humans
Interleukin-23 / genetics*
Mice
NF-E2-Related Factor 2 / antagonists & inhibitors
NF-E2-Related Factor 2 / genetics*
RNA, Small Interfering / genetics
RNA, Small Interfering / pharmacology
STAT3 Transcription Factor / genetics*
Signal Transduction / genetics
Transcriptional Activation / genetics

Substances

Interleukin-23
NF-E2-Related Factor 2
NFE2L2 protein, human
RNA, Small Interfering
STAT3 Transcription Factor
STAT3 protein, human