KDM1A promotes tumor cell invasion by silencing TIMP3 in non-small cell lung cancer cells

Kong, Lingzhi; Zhang, Peng; Li, Wang; Yang, Yan; Wang, Xujun; Chen, Sujun; Yang, Yuxin; Huang, Tianhao; Zhao, Tian; Tang, Liang; Su, Bo; Li, Fēi; Liu, X. Shirley; Zhang, Fan

doi:10.18632/oncotarget.8563

Cited by 41 publications

(44 citation statements)

References 35 publications

(33 reference statements)

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“…It was found that inhibition of LSD1, either by siRNA silencing or SP2509 blockade significantly suppressed cell proliferation, mediated by G1/S cell cycle arrest, along with the accumulation of H3K4me2. These results are consistent with a previous report in non-small cell lung carcinomas, demonstrating that downregulation of LSD1 suppressed cell proliferation and migration capacity 32 . In our mouse model study, SP2509 treatment induced a significant decrease of tumor volume and tumor weight without obvious toxicity.…”

Section: Discussionsupporting

confidence: 94%

LSD1 inhibition suppresses the growth of clear cell renal cell carcinoma via upregulating P21 signaling

Zhu

Wang

Kong

et al. 2019

Acta Pharmaceutica Sinica B

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Histone lysine-specific demethylase 1 (LSD1) has been implicated in the disease progression of several types of solid tumors. This study provides the first evidence showing that LSD1 overexpression occurred in 62.6% (224/358) of clear cell renal cell carcinomas (ccRCC). LSD1 expression was associated with the progression of ccRCC, as indicated by TNM stage ( P =0.006), especially tumor stage ( P =0.017) and lymph node metastasis ( P =0.030). High LSD1 expression proved to be an independent prognostic factor for poor overall survival ( P <0.001) and recurrence-free survival ( P <0.001) of ccRCC patients. We further show that LSD1 inhibition by siRNA knockdown or using the small molecule inhibitor SP2509 suppressed the growth of ccRCC in vitro and in vivo . Mechanistically, inhibition of LSD1 decreased the H3K4 demethylation at the CDKN1A gene promoter, which was associated with P21 upregulation and cell cycle arrest at G1/S in ccRCC cells. Our findings provide new mechanistic insights into the role of LSD1 in ccRCC and suggest the therapeutic potential of LSD1 inhibitors in ccRCC treatment.

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Section: Discussionsupporting

confidence: 94%

LSD1 inhibition suppresses the growth of clear cell renal cell carcinoma via upregulating P21 signaling

Zhu

Wang

Kong

et al. 2019

Acta Pharmaceutica Sinica B

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“…LSD1 is aberrantly upregulated in many human cancer types, such as prostate, breast and lung carcinoma as well as neuroblastoma and leukemia 12 – 16 . Importantly, cancer-related LSD1 overexpression is associated with increased cell proliferation, invasion and migration underscoring the therapeutic potential of LSD1 inhibition 13 , 16 , 17 . In a proliferation screen of cell lines representing various tumor types, acute myeloid leukemia (AML) and SCLC cell lines have been shown to be particularly sensitive to pharmacological LSD1 inhibitors, resulting in cytostatic growth inhibition and advanced differentiation 15 , 18 .…”

Section: Introductionmentioning

confidence: 98%

LSD1 modulates the non-canonical integrin β3 signaling pathway in non-small cell lung carcinoma cells

Lim

Macheleidt

Dalvi

et al. 2017

Sci Rep

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The epigenetic writer lysine-specific demethylase 1 (LSD1) is aberrantly upregulated in many cancer types and its overexpression correlates with poor survival and tumor progression. In this study, we analysed LSD1 function in non-small cell lung cancer adenocarcinomas. Expression profiling of 182 cases of lung adenocarcinoma proved a significant correlation of LSD1 overexpression with lung adenocarcinoma progression and metastasis. KRAS-mutated lung cancer cell clones were stably silenced for LSD1 expression. RNA-seq and comprehensive pathway analysis revealed, that genes related to a recently described non-canonical integrin β3 pathway, were significantly downregulated by LSD1 silencing. Hence, invasion and self-renewal capabilities were strongly decreased. Notably, this novel defined LSD1/integrin β3 axis, was also detected in human lung adenocarcinoma specimens. Furthermore, the linkage of LSD1 to an altered expression pattern of lung-lineage specific transcription factors and genes, which are involved in alveolar epithelial differentiation, was demonstrated. Thus, our findings point to a LSD1-integrin β3 axis, conferring attributes of invasiveness and tumor progression to lung adenocarcinoma.

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“…Egolf et al [65] reported that its downstream targets were involved in epidermal differentiation and cornification processes. Kong et al [66] indicated that treatment with KDM1A inhibitor (2-PCPA) reduced tumour NSCLC cell proliferation and migration. On the other hand, TP63 has been shown as a key player in homeostasis and development of squamous epithelium.…”

Section: Discussionmentioning

confidence: 99%

Molecular Signature of Subtypes of Non-Small-Cell Lung Cancer by Large-Scale Transcriptional Profiling: Identification of Key Modules and Genes by Weighted Gene Co-Expression Network Analysis (WGCNA)

Niemira

Collin

Szałkowska

et al. 2019

Cancers

211

166

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Non-small-cell lung cancer (NSCLC) represents a heterogeneous group of malignancies consisting essentially of adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Although the diagnosis and treatment of ADC and SCC have been greatly improved in recent decades, there is still an urgent need to identify accurate transcriptome profile associated with the histological subtypes of NSCLC. The present study aims to identify the key dysregulated pathways and genes involved in the development of lung ADC and SCC and to relate them with the clinical traits. The transcriptional changes between tumour and normal lung tissues were investigated by RNA-seq. Gene ontology (GO), canonical pathways analysis with the prediction of upstream regulators, and weighted gene co-expression network analysis (WGCNA) to identify co-expressed modules and hub genes were used to explore the biological functions of the identified dysregulated genes. It was indicated that specific gene signatures differed significantly between ADC and SCC related to the distinct pathways. Of identified modules, four and two modules were the most related to clinical features in ADC and SCC, respectively. CTLA4, MZB1, NIP7, and BUB1B in ADC, as well as GNG11 and CCNB2 in SCC, are novel top hub genes in modules associated with tumour size, SUVmax, and recurrence-free survival. Our research provides a more effective understanding of the importance of biological pathways and the relationships between major genes in NSCLC in the perspective of searching for new molecular targets.

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KDM1A promotes tumor cell invasion by silencing TIMP3 in non-small cell lung cancer cells

Cited by 41 publications

References 35 publications

LSD1 inhibition suppresses the growth of clear cell renal cell carcinoma via upregulating P21 signaling

LSD1 inhibition suppresses the growth of clear cell renal cell carcinoma via upregulating P21 signaling

LSD1 modulates the non-canonical integrin β3 signaling pathway in non-small cell lung carcinoma cells

Molecular Signature of Subtypes of Non-Small-Cell Lung Cancer by Large-Scale Transcriptional Profiling: Identification of Key Modules and Genes by Weighted Gene Co-Expression Network Analysis (WGCNA)

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