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EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis.

ABSTRACT: Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy. Overexpression of Enhancer of zeste homolog 2 (EZH2) has been shown to correlate with TNBC's poor prognosis, but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC progression remains elusive. We reveal that selective hyper-activation of functional EZH2 (H3K27me3) over NC-EZH2 alters TNBC metastatic landscape and fosters its peritoneal metastasis, particularly splenic. Instead of H3K27me3-mediated repression of gene expression; here, it promotes KRT14 transcription by attenuating binding of repressor SP1 to its promoter. Further, KRT14 loss significantly reduces TNBC migration, invasion, and peritoneal metastasis. Consistently, human TNBC metastasis displays positive correlation between H3K27me3 and KRT14 levels. Finally, EZH2 knockdown or H3K27me3 inhibition by EPZ6438 reduces TNBC peritoneal metastasis. Altogether, our preclinical findings suggest a rationale for targeting TNBC with EZH2 inhibitors.

SUBMITTER: Verma A

PROVIDER: S-EPMC9708848 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis.

Verma Ayushi A Singh Akhilesh A Singh Manish Pratap MP Nengroo Mushtaq Ahmad MA Saini Krishan Kumar KK Satrusal Saumya Ranjan SR Khan Muqtada Ali MA Chaturvedi Priyank P Sinha Abhipsa A Meena Sanjeev S Singh Anup Kumar AK Datta Dipak D

Nature communications 20221129 1

Triple-Negative Breast Cancer (TNBC) has a poor prognosis and adverse clinical outcomes among all breast cancer subtypes as there is no available targeted therapy. Overexpression of Enhancer of zeste homolog 2 (EZH2) has been shown to correlate with TNBC's poor prognosis, but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC progression remains elusive. We reveal that selective hyper-activation of functional EZH2 (H3K27me3) over NC-EZH2 alters TNB ...[more]

PMID: 36446780

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Project description:Despite evidence that long-term smoking is the leading risk factor for pancreatic malignancies, the underlying mechanism(s) for cigarette-smoke (CS)-induced pancreatic cancer (PC) pathogenesis has not been well established. Our previous studies revealed an aberrant expression of the MUC4 mucin in PC as compared with the normal pancreas, and its association with cancer progression and metastasis. Interestingly, here we explore a potential link between MUC4 expression and smoking-mediated PC pathogenesis and report that both cigarette smoke extract and nicotine, which is the major component of CS, significantly upregulates MUC4 in PC cells. This nicotine-mediated MUC4 overexpression was via the ?7 subunit of nicotinic acetylcholine receptor (nAChR) stimulation and subsequent activation of the JAK2/STAT3 downstream signaling cascade in cooperation with the MEK/ERK1/2 pathway; this effect was blocked by the ?7nAChR antagonists, ?-bungarotoxin and mecamylamine, and by specific siRNA-mediated STAT3 inhibition. In addition, we demonstrated that nicotine-mediated MUC4 upregulation promotes the PC cell migration through the activation of the downstream effectors, such as HER2, c-Src and FAK; this effect was attenuated by shRNA-mediated MUC4 abrogation, further implying that these nicotine-mediated pathological effects on PC cells are MUC4 dependent. Furthermore, the in vivo studies showed a marked increase in the mean pancreatic tumor weight (low dose (100?mg/m(3) total suspended particulate (TSP)), P=0.014; high dose (247?mg/m(3) TSP), P=0.02) and significant tumor metastasis to various distant organs in the CS-exposed mice, orthotopically implanted with luciferase-transfected PC cells, as compared with the sham controls. Moreover, the CS-exposed mice had elevated levels of serum cotinine (low dose, 155.88±35.96?ng/ml; high dose, 216.25±29.95?ng/ml) and increased MUC4, ?7nAChR and pSTAT3 expression in the pancreatic tumor tissues. Altogether, our findings revealed for the first time that CS upregulates the MUC4 mucin in PC via the ?7nAChR/JAK2/STAT3 downstream signaling cascade, thereby promoting metastasis of PC.

Dataset Information

EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis.

Publications

EZH2-H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis.

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