Regulation of KLF4 by posttranslational modification circuitry in endocrine resistance

Zhou, Zhuan; Song, Xinxin; Chi, Junlong; Gius, David; Huang, Yi; Cristofanilli, Massimo; Wan, Yong

doi:10.1016/j.cellsig.2020.109574

Cited by 9 publications

(5 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this work, we have demonstrated that KLF4 is a pivotal causal factor for breast tumor initiation and invasion in both cultured cells and animal models; its abnormal accumulation tightly correlates with poor breast cancer prognosis. In addition, we observed the elevation of KLF4 levels antagonizes killing efficacy for endocrine therapeutic agents as well as various chemotherapy agents in breast cancer treatment (Zhou et al , 2020a). Our new findings highly suggest that KLF4 is a good target for breast cancer treatment.…”

Section: Discussionmentioning

confidence: 93%

New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy

et al. 2020

Self Cite

View full text Add to dashboard Cite

KLF4 plays a critical role in determining cell fate responding to various stresses or oncogenic signaling. Here, we demonstrated that KLF4 is tightly regulated by poly(ADP-ribosyl)ation (PARylation). We revealed the subcellular compartmentation for KLF4 is orchestrated by PARP1-mediated PARylation. We identified that PARylation of KLF4 is critical to govern KLF4 transcriptional activity through recruiting KLF4 from soluble nucleus to the chromatin. We mapped molecular motifs on KLF4 and PARP1 that facilitate their interaction and unveiled the pivotal role of the PBZ domain YYR motif (Y430, Y451 and R452) on KLF4 in enabling PARP1-mediated PARylation of KLF4. Disruption of KLF4 PARylation results in failure in DNA damage response. Depletion of KLF4 by RNA interference or interference with PARP1 function by KLF4 YYR/AAA (a PARylation-deficient mutant) significantly sensitizes breast cancer cells to PARP inhibitors. We further demonstrated the role of KLF4 in modulating homologous recombination through regulating BRCA1 transcription. Our work points to the synergism between KLF4 and PARP1 in tumorigenesis and cancer therapy, which provides a potential new therapeutic strategy for killing BRCA1-proficient triple-negative breast cancer cells.

show abstract

Section: Discussionmentioning

confidence: 93%

New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Interestingly, a recent study showed that miR-196-5p promoted stemness of colorectal cancer cells by activating STAT3 signaling pathway 29 . KLF4, a key factor in pluripotency transcriptional network, not only plays a pivotal role not only in regulating various cellular processes such as cell cycle, apoptosis, and metabolism but also in maintaining the self-renewal capacity of stem cells, including cancer stem cells (CSCs) 31 , 32 . Recently, Wei et al reported that KLF4-induced CSCs contributes to therapeutic resistance in breast cancer 33 .…”

Section: Discussionmentioning

confidence: 99%

MiRNA-296-5p promotes the sensitivity of nasopharyngeal carcinoma cells to cisplatin via targeted inhibition of STAT3/KLF4 signaling axis

Luo,

Wang,

Ren

et al. 2024

Sci Rep

View full text Add to dashboard Cite

Improving drug sensitivity is an important strategy in chemotherapy of cancer and accumulating evidence indicates that miRNAs are involved in the regulation of drug sensitivity, but the specific mechanism is still unclear. Our previous study has found that miR-296-5p was significantly downregulated in nasopharyngeal carcinoma (NPC). Here, we aim to explore whether miR-296-5p is involved in regulating cisplatin sensitivity in NPC by regulating STAT3/KLF4 signaling axis. The cell proliferation and clonogenic capacity of NPC cells were evaluated by CCK8 Assay and plate colony assay, respectively. The Annexin V-FITC staining kit was used to determine and quantify the apoptotic cells using flow cytometry. The drug efflux ability of NPC cells were determined by Rhodamine 123 efflux experiment. The expression of miR-296-5p, apoptosis-related genes and protein in NPC cell lines were detected by qPCR and Western blot, respectively. Animal study was used to evaluate the sensitivity of NPC cells to DDP treatment in vivo. Our results showed that elevated miR-296-5p expression obviously promoted the sensitivity of NPC cells to DDP by inhibiting cell proliferation and clonogenic capacity, and inducing apoptosis. In addition, we found that miR-296-5p inhibited the expression of STAT3 and KLF4 in NPC cells, while overexpression of exogenous STAT3 reversed miR-296-5p-mediated enhancement in cell death of DDP-treated NPC cells. In vivo studies further confirmed that miR-296-5p promotes the sensitivity of NPC cells to DDP treatment. miRNA-296-5p enhances the drug sensitivity of nasopharyngeal carcinoma cells to cisplatin via STAT3/KLF4 signaling pathway.

show abstract

“…Cells were harvested and lysed in radioimmune precipitation assay lysis buffer (Upstate Biotechnology) containing protease inhibitor mixture (Sigma-Aldrich) or 1× SDS loading buffer as described before ( 68 ). The protein concentration was determined using Bio-Rad protein assay reagent.…”

Section: Methodsmentioning

confidence: 99%

“…A standard immunostaining procedure was used to analyze the localization of CD73 and TRIM21 ( 68 ). Cells were seeded and grew on thick slides until they reached 50 to 70% confluence, then washed with PBS, fixed by immersion at room temperature with 4% polyformaldehyde for 20 min, and permeabilized with 0.1% Triton X-100 in PBS at 4°C for 10 min.…”

Section: Methodsmentioning

confidence: 99%

Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity

Chen

Zhu

et al. 2023

Sci. Adv.

Self Cite

View full text Add to dashboard Cite

Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint blockade need to be resolved. Here, we report that elevation of CD73 levels due to its aberrant turnover is correlated with poor prognosis in immune-cold triple-negative breast cancers (TNBCs). We have identified TRIM21 as an E3 ligase that governs CD73 destruction. Disruption of TRIM21 stabilizes CD73 that in turn enhances CD73-catalyzed production of adenosine, resulting in the suppression of CD8 + T cell function. Replacement of lysine 133, 208, 262, and 321 residues by arginine on CD73 attenuated CD73 ubiquitylation and degradation. Diminishing of CD73 ubiquitylation remarkably promotes tumor growth and impedes antitumor immunity. In addition, a TRIM21 high /CD73 low signature in a subgroup of human breast malignancies was associated with a favorable immune profile. Collectively, our findings uncover a mechanism that governs CD73 proteolysis and point to a new therapeutic strategy by modulating CD73 ubiquitylation.

show abstract

Regulation of KLF4 by posttranslational modification circuitry in endocrine resistance

Cited by 9 publications

References 50 publications

New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy

New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy

MiRNA-296-5p promotes the sensitivity of nasopharyngeal carcinoma cells to cisplatin via targeted inhibition of STAT3/KLF4 signaling axis

Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity

Contact Info

Product

Resources

About