Novel Insight into KLF4 Proteolytic Regulation in Estrogen Receptor Signaling and Breast Carcinogenesis

Hu, Dong; Zhou, Zhuan; Davidson, Nancy E.; Huang, Yi; Wan, Yong

doi:10.1074/jbc.m112.343566

Cited by 31 publications

(31 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with previous report, 25 KLF4 showed a significant increase in breast cancer tissues compared with adjacent normal tissues. And FBXO32 was remarkably down-regulated in the same samples (Figure 6d).…”

Section: Resultssupporting

confidence: 93%

“…24 and Hu et al . 25 identified pVHL as a protein that governs KLF4 turnover and illustrated that estrogen-induced downregulation of pVHL facilitates accumulation of KLF4 in breast cancer cells. Suppression of pVHL in response to estrogen signaling pathway results in elevation of KLF4 protein and subsequent mitotic effect.…”

Section: Discussionmentioning

confidence: 99%

“…Given the short half-life of KLF4, we focused on its posttranslational regulation, especially the ubiquitination regulation. The E3 ligase Cdh1-anaphase-promoting complex, 22 β-TrCP 23 and pVHL 24,25 are reported to mediate KLF4 ubiquitination and degradation. Anaphase-promoting complex governs transforming growth factor-β-induced KLF4 proteolysis in colon cancer cells.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

et al. 2017

View full text Add to dashboard Cite

Krüppel-like factor 4 (KLF4, GKLF) is a zinc-finger transcription factor involved in a large variety of cellular processes, including apoptosis, cell cycle progression, as well as stem cell renewal. KLF4 is critical for cell fate decision and has an ambivalent role in tumorigenesis. Emerging data keep reminding us that KLF4 dysregulation either facilitates or impedes tumor progression, making it important to clarify the regulating network of KLF4. Like most transcription factors, KLF4 has a rather short half-life within the cell and its turnover must be carefully orchestrated by ubiquitination and ubiquitin–proteasome system. To better understand the mechanism of KLF4 ubiquitination, we performed a genome-wide screen of E3 ligase small interfering RNA library based on western blot and identified SCF-FBXO32 to be a new E3 ligase, which is responsible for KLF4 ubiquitination and degradation. The F-box domain is critical for FBXO32-dependent KLF4 ubiquitination and degradation. Furthermore, we demonstrated that FBXO32 physically interacts with the N-terminus (1–60 aa) of KLF4 via its C-terminus (228–355 aa) and directly targets KLF4 for ubiquitination and degradation. We also found out that p38 mitogen-activated protein kinase pathway may be implicated in FBXO32-mediated ubiquitination of KLF4, as p38 kinase inhibitor coincidently abrogates endogenous KLF4 ubiquitination and degradation, as well as FBXO32-dependent exogenous KLF4 ubiquitination and degradation. Finally, FBXO32 inhibits colony formation in vitro and primary tumor initiation and growth in vivo through targeting KLF4 into degradation. Our findings thus further elucidate the tumor-suppressive function of FBXO32 in breast cancer. These results expand our understanding of the posttranslational modification of KLF4 and of its role in breast cancer development and provide a potential target for diagnosis and therapeutic treatment of breast cancer.

show abstract

Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

et al. 2017

View full text Add to dashboard Cite

show abstract

“…As shown in Fig. 2A, while USP11 expression is relatively low in mammary epithelial cell MCF10A and moderate in Her2 positive breast cancer cell SKBR3, a significant accumulation of USP11 is observed in triple negative and ER positive type of breast cancer cell lines, including MDA-MB-231, MDA-MB-468, MCF7 and T47D (Zhou et al, 2013, Hu et al, 2012). Furthermore, tissue arrays of 65 breast invasive ductal carcinoma and 48 adjacent normal tissue specimens were examined by IHC with anti-USP11 and visualized by DAB staining (He et al, 2015).…”

Section: Resultsmentioning

confidence: 82%

Regulation of XIAP Turnover Reveals a Role for USP11 in Promotion of Tumorigenesis

et al. 2017

Self Cite

View full text Add to dashboard Cite

The emerging regulatory role of deubiquitinases (DUBs) has been implicated in various fundamental processes and pathogenesis. To determine the pivotal role that DUBs play in mediating tumorigenesis, we have performed a non-biased screen of 67 human DUBs based on a mammary cell transformation assay. This led to the identification of USP11 as a critical determinant of mammary tumor initiation and progression. Using an approach of protein complex purification coupled with mass spectrometry, we further identified XIAP to be a target for USP11. We demonstrated that, while depletion of XIAP attenuates cell transformation, elevated USP11 significantly promotes the tumor colony formation through stabilization of XIAP. Molecular modeling coupled with mutagenesis analyses further revealed that Leu207 on the BIR2 domain of XIAP facilitates its interaction with USP11. Stabilization of XIAP due to its deubiquitylation by USP11 leads to the inhibition of cell anoikis and apoptosis, which in turn promotes tumorigenesis. Finally, immunohistochemical staining revealed that aberrant accumulation of USP11 correlates with elevated levels of XIAP in breast cancer tissues. We therefore propose that aberrant USP11, via stabilization of XIAP, promotes tumor initiation and progression.

show abstract

“…In order to understand why BLIMP1 levels were reduced in female risk allele carriers only, we compared the message level of KLF4 in MO-DCs prepared from female and male donors. KLF4 has been shown to be positively regulated by estrogen signals in breast cancer cells (38), suggesting that there might be a difference in KLF4 levels between females and males. There was no difference in the level of KLF4 mRNA analyzed from MO-DCs from all (including both risk and nonrisk allele carriers) female and male donors (data not shown); however, higher levels were observed in MO-DCs from female risk-allele carriers compared with female nonrisk carriers, but higher levels were not observed in MO-DCs from male risk carrier compared to male nonrisk allele carriers ( Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

Kruppel-like factor4 regulates PRDM1 expression through binding to an autoimmune risk allele

Jang¹,

Chen²,

Gregersen³

et al. 2017

JCI Insight

View full text Add to dashboard Cite

Novel Insight into KLF4 Proteolytic Regulation in Estrogen Receptor Signaling and Breast Carcinogenesis

Cited by 31 publications

References 63 publications

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

Regulation of XIAP Turnover Reveals a Role for USP11 in Promotion of Tumorigenesis

Kruppel-like factor4 regulates PRDM1 expression through binding to an autoimmune risk allele

Contact Info

Product

Resources

About