Histone methyltransferase KMT2D sustains prostate carcinogenesis and metastasis via epigenetically activating LIFR and KLF4

Lv, Shidong; Ji, Liyan; Chen, Bin; Liu, Shuqiang; Lei, Chengyong; Liu, Xi; Qi, Xiaoxiao; Wang, Ying; Leung, Elaine Lai‐Han; Wang, Hongyi; Zhang, Lin; Yu, Xiaoming; Liu, Zhongqiu; Wang, Qiang; Lu, Linlin

doi:10.1038/s41388-017-0026-x

Cited by 100 publications

(90 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The present study adds to evidence supporting LIFR involvement in mediating resistance by demonstrating that overexpression of LIFR leads to STAT3 activation and confers resistance to T‐DM1 in HER2‐positive breast cancer cells. LIFR expression is regulated by many complex mechanisms, such as gene copy number changes, histone acetylation or methylation at the LIFR gene promoter, microRNA and so on . We found that the gene copy number of LIFR was not changed in BT‐474/KR cells (Figure ), and the exact mechanisms underlining LIFR overexpression in BT‐474/KR cells needed further research.…”

Section: Discussionmentioning

confidence: 86%

“…LIFR expression is regulated by many complex mechanisms, such as gene copy number changes, histone acetylation or methylation at the LIFR gene promoter, microRNA and so on. [31][32][33] We found that the gene copy number of LIFR was not changed in BT-474/KR cells ( Figure S1), and the exact mechanisms underlining LIFR overexpression in BT-474/KR cells needed further research.…”

Section: Stat3 Inhibition Overcomes T-dm1 Resistance In Vivomentioning

confidence: 95%

See 1 more Smart Citation

STAT3 activation confers trastuzumab‐emtansine (T‐DM1) resistance in HER2‐positive breast cancer

Wang

Gao

et al. 2018

Cancer Science

View full text Add to dashboard Cite

Trastuzumab‐emtansine (T‐DM1) is an antibody‐drug conjugate that has been approved for the treatment of human epidermal growth factor receptor 2 (HER2)‐positive metastatic breast cancer. Despite the remarkable efficacy of T‐DM1 in many patients, resistance to this therapeutic has emerged as a significant clinical problem. In the current study, we used BT‐474/KR cells, a T‐DM1‐resistant cell line established from HER2‐positive BT‐474 breast cancer cells, as a model to investigate mechanisms of T‐DM1 resistance and explore effective therapeutic regimens. We show here for the first time that activation of signal transducer and activator of transcription 3 (STAT3) mediated by leukemia inhibitory factor receptor (LIFR) overexpression confers resistance to T‐DM1. Moreover, secreted factors induced by activated STAT3 in resistant cells limit the responsiveness of cells that were originally sensitive to T‐DM1. Importantly, STAT3 inhibition sensitizes resistant cells to T‐DM1, both in vitro and in vivo, suggesting that the combination T‐DM1 with STAT3‐targeted therapy is a potential treatment for T‐DM1‐refractory patients.

show abstract

Section: Discussionmentioning

confidence: 86%

Section: Stat3 Inhibition Overcomes T-dm1 Resistance In Vivomentioning

confidence: 95%

STAT3 activation confers trastuzumab‐emtansine (T‐DM1) resistance in HER2‐positive breast cancer

Wang

Gao

et al. 2018

Cancer Science

View full text Add to dashboard Cite

show abstract

“…Hillman RT et al reported that inactivation resulted from truncating mutation of KMT2D gene tends to recurrence of adult‐type granulosa cell tumors of the ovary . Furthermore, Lv S et al detected anti‐metastasis outcome of prostate cancer cells after knockdown of MLL2 . Our data obviously showed that high expressed MLL2 TIL in invasive tumor front was vulnerable to 5‐year postoperative recurrence and metastasis for early‐stage OSCC patients.…”

Section: Discussionmentioning

confidence: 50%

Tumor‐infiltrating lymphocyte‐derived MLL2 independently predicts disease‐free survival for patients with early‐stage oral squamous cell carcinoma

Zhu

Ding

et al. 2019

J Oral Pathology Medicine

View full text Add to dashboard Cite

Background MLL2 (mixed‐lineage leukemia 2) is recognized as an essential role in regulating histone 3 lysine 4 tri‐methylation (H3K4me3) in mammalian cells. It is frequently mutated to promote developmental diseases and tumor initiation. However, the expression pattern of MLL2 and its clinical significance for patients with early‐stage oral squamous cell carcinoma (OSCC) remain totally unknown. Methods Eighty‐five samples of primary early‐stage OSCC were enrolled in this retrospective study, and immunohistochemistry (IHC) was performed to detect the spatial pattern of MLL2. The diagnostic and prognostic value of MLL2 were assessed. Results MLL2 was widely expressed in tumor cells (TCs), fibroblast‐like cells (FLCs), and tumor‐infiltrating lymphocytes (TILs), both in tumor center and invasive tumor front, and showed no distributive heterogeneity. Moreover, regardless of cell types and microlocalization, patients with high expressed MLL2 had increased depth invasion of tumor (DOI). Besides, upregulation of MLL2TC and MLL2TIL in tumor center were both associated with poor differentiation, but showed no correlation with tumor growth with comparable Ki‐67 levels. Prognostic analysis indicated that early‐stage OSCC patients with enhanced MLL2TIL in invasive tumor front were susceptible to occur postoperative metastasis and recurrence. Indeed, patients with higher expressed MLL2TIL showed shorter overall survival (OS) and disease‐free survival (DFS), and MLL2TIL in invasive tumor front was an independent risk factor of DFS. Conclusion TIL‐derived MLL2 in invasive tumor front was an independent prognostic factor of DFS for early‐stage OSCC patients.

show abstract

“…A549 and H1299 cells were seeded in 15 mm confocal dish (3 × 10 4 cells/well) and allowed to grow overnight, and then cells were treated with vehicle or EVO (4, 8, and 16 μM for A549 cells and 1, 2, and 4 μM for H1299 cells, respectively) for 48 h. After harvested, cells were fixed in 4% cold paraformaldehyde, and then incubated with Notch3 primary antibody (1:1000, v/v) at 4°C overnight. After washing with PBS, cells were incubated with Alexa Fluor ® conjugated secondary antibodies (1:500, v/v) at room temperature for 1 h ( Lv et al, 2017 ). Images were captured using Leica TCS SP8 confocal microscope (Leica, GER).…”

Section: Methodsmentioning

confidence: 99%

Evodiamine, a Novel NOTCH3 Methylation Stimulator, Significantly Suppresses Lung Carcinogenesis in Vitro and in Vivo

Xia

Deng

et al. 2018

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Lung cancer is a leading cause of cancer-related deaths worldwide. NOTCH3 signaling is mainly expressed in non-small cell lung carcinoma (NSCLC), and has been proposed as a therapeutic target of NSCLC. While, few agents for preventing or treating NSCLC via targeting NOTCH3 signaling are used in modern clinical practice. Evodiamine (EVO), an alkaloid derived from Euodiae Fructus, possesses low toxicity and has long been shown to exert anti-lung cancer activity. However, the underlying anti-lung cancer mechanisms of EVO are not yet fully understood. In this study, we explored the involvement of NOTCH3 signaling in the anti-lung cancer effects of EVO. Urethane-induced lung cancer mouse model and two NSCLC cell models, A549 and H1299, were used to evaluate the in vivo and in vitro anti-lung cancer action of EVO. A DNA methyltransferase inhibitor was employed to investigate the role of NOTCH3 signaling in the anti-lung cancer effects of EVO. Results showed that EVO potently reduced tumor size and tumor numbers in mice, and inhibited NOTCH3 in the tumors. EVO also dramatically reduced cell viability, induced G2/M cell cycle arrest, inhibited cell migration and reduced stemness in cultured NSCLC cells. Mechanistic studies showed that EVO potently inhibited NOTCH3 signaling by activation of DNMTs-induced NOTCH3 methylation. Importantly, inhibition of NOTCH3 methylation in NSCLC cells diminished EVO’s anti-NSCLC effects. Collectively, EVO, a novel NOTCH3 methylation stimulator, exerted potent anti-lung cancer effects partially by inhibiting NOTCH3 signaling. These findings provide new insight into the EVO’s anti-NSCLC action, and suggest a potential role of EVO in lung cancer prevention and treatment.

show abstract

Histone methyltransferase KMT2D sustains prostate carcinogenesis and metastasis via epigenetically activating LIFR and KLF4

Cited by 100 publications

References 53 publications

STAT3 activation confers trastuzumab‐emtansine (T‐DM1) resistance in HER2‐positive breast cancer

STAT3 activation confers trastuzumab‐emtansine (T‐DM1) resistance in HER2‐positive breast cancer

Tumor‐infiltrating lymphocyte‐derived MLL2 independently predicts disease‐free survival for patients with early‐stage oral squamous cell carcinoma

Evodiamine, a Novel NOTCH3 Methylation Stimulator, Significantly Suppresses Lung Carcinogenesis in Vitro and in Vivo

Contact Info

Product

Resources

About