KLF17 empowers TGF-β/Smad signaling by targeting Smad3-dependent pathway to suppress tumor growth and metastasis during cancer progression

Cell Death & Disease
Amjad AliJ Xiao

Abstract

Inhibition of tumor suppressive signaling is linked to cancer progression, metastasis and epithelial-mesenchymal transition (EMT). Transforming growth factor-β1 (TGF-β)/Smad signaling plays an important role in tumor suppression. Kruppel-like-factor 17 (KLF17) is a negative regulator of metastasis and EMT. However, underlying mechanisms leading to tumor suppressive and anti-metastatic function of KLF17 still remains unknown. Here, we show that KLF17 plays an integral role in potentiating TGF-β/Smad signaling via Smad3-dependent pathway to suppress tumor progression. Intriguingly, TGF-β/Smad3 signaling induces KLF17 expression, generating a positive feedback loop. TGF-β/Smad3-KLF17 loop is critical for anti-metastasis and tumor inhibition in cancer cells. Mechanistically, silencing KLF17 reduced Smad3-DNA complex formation on Smad binding element (SBE) and affects the expression of TGF-β/Smad target genes. Moreover, KLF17 alters Smad3 binding pattern on chromatin. KLF17 regulates TGF-β target genes that are Smad3-dependent. Smad3 and KLF17 physically interact with each other via KLF17 responsive elements/SBE region. Intriguingly, TGF-β stimulates the recruitment of KLF17 on chromatin to subsets of metastasis-associated genes. Fu...Continue Reading

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Citations

Dec 31, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Yang LiChengyuan Ma
Dec 17, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Qi-Han FuTing-Bo Liang
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Oct 17, 2019·Cells·Shuo TuXiaohua Yan
Jul 29, 2020·Proceedings of the National Academy of Sciences of the United States of America·Can WangQingyu Wu
Apr 23, 2020·Acta Biochimica Et Biophysica Sinica·Yining LiXiaohua Yan
Dec 20, 2020·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Kegui ZhangXiaohua Yan
Mar 7, 2021·International Journal of Molecular Sciences·Joshua AltschulerNatasha Kyprianou
Oct 8, 2021·Reviews on Environmental Health·Xiaotong YangLiming Li
Nov 6, 2021·The Journal of International Medical Research·Shaoyi LiZhaojie An

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Datasets Mentioned

BETA
GSE6764

Methods Mentioned

BETA
electrophoretic mobility shift assay
ChIP
transfection
immunoprecipitation
scraping
PCR
electrophoresis
column chromatography
Assay
flow cytometry

Software Mentioned

R
arrayQualityMetrics
affyQCReport
affy

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