CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

Qu, Huinan; Qi, Da; Wang, Xinqi; Dong, Yuan; Qiu, Jin; Wei, Junyuan; Quan, Chengshi

doi:10.3390/ijms23010129

Cited by 16 publications

(9 citation statements)

References 44 publications

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“…In addition, the energy required for tumor cell invasion and migration can be continuously supported by aerobic glycolysis. Reprogramming glucose metabolism from oxidative phosphorylation to aerobic glycolysis to promote cancer growth, a phenomenon known as the 'Warburg effect,' is a specific hallmark of tumor cell metabolism (8). Various enzymes and signaling molecules involved in aerobic glycolysis have been reported to have an important role in the malignant development of tumors (9).…”

Section: Introductionmentioning

confidence: 99%

YY1 transcription factor induces proliferation and aerobic glycolysis of neuroblastoma cells via LDHA regulation

et al. 2022

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The present study investigated the effect of transcription factor yin yang 1 (YY1) on aerobic glycolysis and cell proliferation in neuroblastoma and its mechanism. Neuroblastoma cell lines were used to investigate the association between YY1 and lactate dehydrogenase A (LDHA) expression. Cell Counting Kit (CCK)-8 and clone formation experiments were used to detect the cell viability. The interaction of YY1 and LDHA was detected using chromatin immunoprecipitation assay. Glucose uptake, intra/extracellular lactate and pyruvate and LDHA expression were evaluated using standard methods. Reverse transcription quantitative PCR, western blotting and gene overexpression or silencing were undertaken to explore the biological effects and underlying mechanisms of transcriptional regulators in NB cells. The results demonstrated that YY1 was significantly upregulated in neuroblastoma cell lines. The results of aerobic glycolysis and CCK-8 indicated that YY1 significantly promoted the proliferation and aerobic glycolysis of neuroblastoma cells. In addition, chromatin immunoprecipitation-PCR results demonstrated that YY1 was directly bound to the promoter LDHA. Overexpression of LDHA could reverse the inhibitory effect of sh-YY1 on aerobic glycolysis and proliferation of neuroblastoma cells. In conclusion, YY1 could induce aerobic glycolysis and proliferation of neuroblastoma cell lines, and may directly mediate the regulation of LDHA. These findings may provide novel insight for the treatment of neuroblastoma.

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Section: Introductionmentioning

confidence: 99%

YY1 transcription factor induces proliferation and aerobic glycolysis of neuroblastoma cells via LDHA regulation

et al. 2022

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“…Confocal images of TAZ localization showed that hiltonol induced a significant cytoplasmic sequestration of TAZ, corresponding to the dose of hiltonol, in both NK-92 ( Figure 2A ) and hNK cells ( Figure 2B ), but without affecting cell viability ( Figure S3B ). Interestingly, in control resting NK cells, TAZ was homogeneously present in both the cytoplasm and nucleus of NK cells, in contrast to being predominantly present in the nucleus of other adherent cell types [39][40] . To corroborate our observations, we treated NK-92 and hNK cells with hiltonol and performed imaging flow analysis to empirically quantify the overlap signal of nuclear stain (DAPI) to TAZ ( Figure 2C-F ).…”

Section: Resultsmentioning

confidence: 99%

Natural Killer cell contractility and cytotoxicity is driven by TLR3 agonist-mediated TAZ cytoplasmic sequestration

Wong

Xia

Shao

et al. 2023

Preprint

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The evolutionarily conserved YAP/TAZ mechano-responsive transcription cofactors regulate development and tumorigenesis. Here, we show for the first time that human natural killer (NK) cells specifically express TAZ but not YAP, and TAZ serves to limit NK cytotoxicity. The TLR3 agonist, hiltonol, was able to trigger cytoplasmic sequestration of TAZ, which increased NK cytotoxicity. Mechanistically, a low dose of hiltonol enhanced the intracellular contractility of NK cells accompanied by an increase in active RhoA and myosin light chain phosphorylation, conceivably through an increase in ERK1/2 activation-dependent ROS production. Importantly, we showed that the dissociation of LATS1 from actin upon activation of contractility, is required to sequester TAZ in the cytoplasm. Functionally, hiltonol also reduced the NK cell surface inhibitory receptors, KIR3DL1 through c-Myc inhibition and PD-1 through enhanced contractility. Direct inhibition of c-Myc promoted NK cytotoxicity against K562 lymphoblast. We corroborated our findings by coculturing hiltonol-pretreated NK cells with breast and lung cancer cells, and demonstrated increased NK-mediated cancer killing, which conceivably occurred via sequestration of TAZ to the cytoplasm which facilitated NK cytotoxicity. Our findings pave the way for ex vivo rejuvenation of NK cells for in vivo immunotherapies, which could involve a cocktail of hiltonol and c-Myc inhibitor.

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“…The IF assay was performed as previously described [8]. Antibodies used in IF were listed in Supplementary materials.…”

Section: Immunofluorescent Staining (If)mentioning

confidence: 99%

“…CLDN6 is a member of the CLDNs family, containing four transmembrane helices and a COOHterminal PDZ-binding motif (PBM) [1]. In addition to traditional functions of CLDN6 in permeability regulation and barrier formation [2][3][4][5], CLDN6 connects proteins containing PDZ domain or PBM through its PBM, regulating intracellular signaling pathways to affect the malignant phenotype of cancer [6][7][8][9][10][11]. Previously, we have cloned CLDN6 as a candidate suppressor gene of breast cancer from COP rat mammary epithelial cells for the first time [12].…”

Section: Introductionmentioning

confidence: 99%

CLDN6 inhibits breast cancer metastasis through WIP-dependent actin cytoskeleton-mediated autophagy

Dong

Qiu

Sun

et al. 2023

J Exp Clin Cancer Res

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Background As a breast cancer suppressor gene, CLDN6 overexpression was found to inhibit breast cancer metastasis in our previous studies, but the specific mechanism remains unclear. This study aimed to clarify the role and mechanism of CLDN6 in inhibiting breast cancer metastasis. Methods Western blot, immunofluorescence and transmission electron microscopy were performed to detect autophagy. Wound healing, transwell assays and lung metastasis mouse models were used to examine breast cancer metastasis. Phalloidin staining and immunofluorescent staining were used to observe actin cytoskeleton. mRNA seq, RT-PCR, western blot, chromatin immunoprecipitation, dual luciferase reporter assay, co-immunoprecipitation and immunofluorescence were performed to define the molecular mechanism. The expression levels and clinical implication of CLDN6, WIP and LC3 in breast cancer tissues were evaluated using immunohistochemistry. Results We demonstrated that CLDN6 inhibited breast cancer metastasis through autophagy in vitro and vivo. We unraveled a novel mechanism that CLDN6 regulated autophagy via WIP-dependent actin cytoskeleton assembly. Through its PDZ-binding motif, overexpressed CLDN6 interacted with JNK and upregulated JNK/c-Jun pathway. C-Jun promoted WIP expression at the transcriptional level. Notably, we observed c-Jun transcriptionally upregulated CLDN6 expression, and there was a positive feedback loop between CLDN6 and JNK/c-Jun. Finally, we found that CLDN6, WIP and LC3 expression correlated with each other, and WIP expression was significantly associated with lymph node metastasis of breast cancer patients. Conclusions The data provide a new insight into the inhibitory effects of CLDN6-mediated autophagy on breast cancer metastasis, and revealed the new mechanism of CLDN6 regulating autophagy through WIP-dependent actin cytoskeleton. Our findings enrich the theoretical basis for CLDN6 as a potential biomarker for breast cancer diagnosis and therapy.

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CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

Cited by 16 publications

References 44 publications

YY1 transcription factor induces proliferation and aerobic glycolysis of neuroblastoma cells via LDHA regulation

YY1 transcription factor induces proliferation and aerobic glycolysis of neuroblastoma cells via LDHA regulation

Natural Killer cell contractility and cytotoxicity is driven by TLR3 agonist-mediated TAZ cytoplasmic sequestration

CLDN6 inhibits breast cancer metastasis through WIP-dependent actin cytoskeleton-mediated autophagy

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