A pan-cancer study of the role of lysine specific demethylase 1 (LSD1) in human cancers

doi:10.21203/rs.3.rs-1988151/v1

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A pan-cancer study of the role of lysine specific demethylase 1 (LSD1) in human cancers

https://doi.org/10.21203/rs.3.rs-1988151/v1

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Objectives: To conduct a pan-cancer analysis of a relationship between LSD1 and cancer.

Setting: Although increasing evidence from cell- or animal-based research supports the existence of a relationship between LSD1 and cancer, there is no pan-cancer analysis.

Data sources: Databases, including TCGA, and GEO.

Results: On the basis of the TCGA and GEO datasets, we first found that LSD1 may contribute to tumorigenesis across 34 tumor types. LSD1 is expressed in most cancers at a higher level than in normal tissues, and there are distinguishable differences between the LSD1 expression and prognosis of patients. We found that the phosphorylation level of S166 is highly expressed in several tumors, including breast cancer, uterine corpus endometrial carcinoma and lung adenocarcinoma. There was an association between the expression of LSD1 and the infiltration of cancer-associated fibroblasts in BRCA, CESC, ESCA, HNSC, KIRC, LUAD, LUSC, PAAD and PCPG. In addition, RNA transport, mRNA surveillance pathways, and spliceosome -associated functions are also involved in the molecular mechanisms of LSD1.

Conclusions: This pan-cancer study provides a fairly comprehensive description of the oncogenic roles of LSD1 in a wide variety of tumors.

Considering the complexity of tumor formation, more and more researchers pay particular attention to the expression of any gene of interest and its relationship with prognosis and potential functional mechanisms. There exist functional genomics data sets of different tumors in the public TCGA dataset and the available GEO dataset and thus enable us to conduct a pan-cancer analysis [1–4].

Lysine-specific demethylase 1 (LSD1) is the first known histone demethylase, and it controls gene expression at the transcriptional and post-transcriptional level [5, 6]. Leukemia and several types of solid tumors, including non-small cell lung carcinoma (NSCLC) [7–9], neuroblastoma [10, 11], pancreatic cancer [12, 13], prostate cancer [14, 15], and breast cancer [16, 17], are reported to be associated with LSD1. LSD1 inhibition reduces or inhibits the growth of most tumor cells, while overexpression of LSD1 leads to tumorigenesis through chromatin modification [18–21]. On the basis of big clinical data, there is still no pan-cancer evidence linking LSD1 and various tumors.

In this study, we conducted a pan-cancer analysis of LSD1 using the GEO and TCGA databases for the first time. This analysis is based on several factors, including gene expression, genetic modification, survival status, immune infiltration and protein phosphorylation and relevant pathway to investigate the potential molecular mechanism of LSD1 in the pathogenesis or clinical prognosis of various cancer types.

Gene expression analysis

We analyzed the difference expression of LSD1 between various tumors and adjacent normal tissues in TCGA datasets by entering LSD1 in the "Gene_DE" module of TIMER2 (tumor immune estimation resource, version 2) web (http://timer.cistrome.org/). As for tumors with no normal or with very limited normal tissues [for example, TCGA-ACC (adrenocortical carcinoma), TCGA-LAML (acute myeloid leukemia), etc.], we utilizing the "Expression analysis-Box Plots” module of GEPIA2 (Gene Expression Profiling Interactive Analysis, version 2) web server (http://gepia2.cancer-pku.cn/#analysis) to calculated the box plots representing the differences in the expression of these tumor tissues compared to the corresponding normal tissues of the GTEx (Genotype-Tissue Expression) dataset, according to the settings of P-value cutoff = 0.01, log2FC (fold change) cutoff = 1, and “Match TCGA normal and GTEx datasets” [22]. Moreover, we got violin plots of LSD1 expression at all TCGA tumor stages (stage I, stage II, stage III, and stage IV) using the “Pathological Stage Plot” module of HEPIA2. As a basis for the box plots or violin plots, log2 [TPM (Transcripts per million) + 1] transformed expression data were used. Analysis of the protein expression data in the CPTAC (Clinical proteomic tumor analysis consortium) dataset was carried out using the UALCAN portal (http://ualcan.path.uab.edu/analysis-prot.html), a web-based resource for analyzing cancer Omics data [23]. By entering "LSD1", we could determine the expression level of the total protein or phosphoprotein (with phosphorylation at the Y109, Y150, S426, T431, S645, S781, and S909 sites) of LSD1 in primary tumors and normal tissues, respectively. There are six tumor datasets available, including breast cancer, ovarian cancer, colon cancer, clear cell RCC (Renal cell carcinoma), UCEC (Uterine corpus endometrial carcinoma), and LUAD (Lung adenocarcinoma).

Survival prognosis analysis

By using the "Survival Map" module of GEPIA2, we calculated OS (Overall survival) and DFS (Disease-free survival) significance maps for LSD1 in TCGA tumors [22]. In order to separate the high-expression cohort from the low-expression cohort, cutoff-high (50%) and cutoff-low (50%) values were used as expression thresholds. In our hypothesis test, we used the log-rank test, and survival plots were obtained using the "Survival Analysis" module of GEPIA2.

Genetic alteration analysis

Using the cBioPortal web (https://www.cbioportal.org/), we selected the "TCGA Pan Cancer Atlas Studies" and entered "LSD1" to find out the genetic alteration characteristics of LSD1 [24, 25]. In the "Cancer Types Summary" module, the data showed an alteration frequency, mutation type, and CNA (Copy number alteration) for each TCGA tumor type. With the "Mutations" module, you can see the mutated sites of LSD1 in the schematic diagram of the protein structure or in the 3D (three-dimensional) structure. With the "Comparison" module, data was obtained on the differences in overall, disease-free, progression-free, and disease-free survival between TCGA cancer cases with and without LSD1 genetic alteration. A Kaplan-Meier plot with log-rank P-value were generated, as well.

Immune infiltration analysis

On the TIMER2 web server, we used the “Immune-Gene” module to analyze the relationship between LSD1 expression and immune infiltrates among all TCGA cancer cells. On the basis of our analyses, we selected immune cells including CD8 + T-cells and cancer-associated fibroblasts. The TIMER, CIBERSORT, CIBERSORT-ABS, QUANTISEQ, XCELL, MCPCOUNTER and EPIC algorithms were employed for immune infiltration estimations detection. By using the purity-adjusted Spearman's rank correlation test, P-values and partial correlation (cor) values were calculated. Heatmaps and scatter plots were used to illustrate the data. Kaplan-Meier plots with P-values were also performed [26].

LSD1-related gene enrichment analysis

When logged in to the STRING dataset (https://string-db.org/), we searched for a single protein name ("LSD1") and organism ("Homo sapiens"). Our next step is to set some main parameters: the minimum required interaction score [“Low confidence (0.150)”], the meaning of network edges (“evidence”), the maximum number of interactors to show (“no more than 50 interactors” in 1st shell) and active interaction sources (“experiments”). On the basis of the datasets derived from all TCGA tumor and normal tissues, we retrieved the top 100 LSD1-correlated targeting genes using the "Similar Gene Detection" module of GEPIA2. As part of the correlation analysis in GEPIA2, a pairwise gene Pearson correlation was conducted between LSD1 and selected genes. The log2 TPM was applied in the dot plot. P-values and correlation coefficients (R) were displayed. Moreover, we utilized the "Gene_Corr" module of TIMER2 to output the heatmaps for the selected genes with partial correlation and P-value for a purity-adjusted Spearman’s rank correlation test. We used Jvenn, an interface that visualizes interactive Venn diagrams, to complete the intersection analysis between LSD1-binding and interacted genes [27]. Furthermore, KEGG (Kyoto encyclopedia of genes and genomes) pathway analysis was also performed on the two sets of data. Essentially, we uploaded the gene lists to DAVID (Database for annotation, visualization, and integrated discovery) and analyzed the functional annotation charts based on the selected identifier (“OFFICIAL_GENE_SYMBOL”) and species (“Homo sapiens”) settings. Finally, we visualized the enriched pathways using the R packages "tidyr" and "ggplot2". Furthermore, we also performed an analysis of GO (Gene ontology) enrichment using the "clusterProfiler" R package. With the cnetplot function, the data for BP (Biological process), CC (Cellular component), and MF (Molecular function) are visualized as cnetplots. (circular = F, colorEdge = T, node_label = T). This analysis was performed using the R language software [R-3.6.3, 64-bit] (https://www.r-project.org/). We considered two-tailed P < 0.05 to be statistically significant.

Analysis of expression data for LSD1

In our study, we analyzed the expression levels of human LSD1 across various TCGA tumors using the TIMER2 approach. As shown in Fig. 1A, The expression of LSD1 in the tumor tissues of BLCA (Bladder transitional cell cancer), BRCA (Breast invasive cancer), CESC (Cervical and endocervical carcinomas), CHOL (Cholangiocarcinoma), CRC (Colorectal carcinoma), EC (Esophageal cancer), GBM (Glioblastoma multiforme), SCCHN (Squamous cell carcinoma of the head and neck), LIHC (Liver hepatocellular cancer), LUAD (Lung adenomatous carcinoma), LUSC (Lung squamous cell cancer), PCA (prostatic cancer), READ (Rectum adenomatous carcinoma), STAD (Stomach adenomatous carcinoma) and CECU (Corpus endometrial carcinoma of the uterus) is higher than the adjacent control tissues.

In the GTEx dataset, we included the normal tissue as controls, the expression of LSD1 was compared between normal tissues and tumor tissues of BRCA (Breast invasive carcinoma), DLBC (Lymphoid tumor diffuse large B-cell lymphoma), LGG (Low grade glioma of the brain), THYM (Medullary thymoma), and UCS (Uterine Carcinosarcoma). The results showed a significant difference for these tumors (Fig. 1B).

We investigated the expression levels of LSD1 total protein using the CPTAC dataset, the results showed that the expression of LSD1 total protein was higher in the primary tissues of breast carcinoma, colon carcinoma, ovarian carcinoma, clear cell RCC, LUAD and UCEC (Fig. 1C) than in normal tissues. With HEPIA2, the "Pathological Stage Plot" module, it was observed that LSD1 expression correlated with pathological stages in cancers including HNSC, LIHC, OV (Ovarian serous cystadenocarcinoma), and SKCM (Melanoma of the skin and cutaneous) (Fig. 1D, all P < 0.05) but not in other types of cancer.

Survival analysis data

According to the expression levels of LSD1, we classified cancer cases into high expression group and low expression group, and mainly used TCGA and GEO datasets respectively to study the relationship between LSD1 expression and prognosis of patients with different tumors. As shown in Fig. 2A, high expression of LSD1 genes was associated with poor overall survival for cancers of ACC (P = 0.003), LIHC (P = 0.0058), and SARC (P = 0.012), while a low expression of LSD1 genes was associated with poor survival for COAD (Fig. 2A, P = 0.025) and KIRC (Fig. 2A, P = 0.026). According to the DFS (Disease-free Survival) analysis data (Fig. 2B), high LSD1 expression predicts a poor prognosis for ACC (P = 0.00015), KICH (P = 0.045), LGG (P = 0,017), and LIHC (P = 0.021) cases in TCGA. In addition, low expression of LSD1 gene was associated with poor prognosis of KIRC OS (Fig. 2B, P = 0.016).

Genetic alteration analysis data

We investigated the LSD1 genetic alteration status in different tumor samples from the TCGA cohorts in our study. As shown in Fig. 3A, the most frequent abnormalities of LSD1 (> 3%) were noted in patients with uterine corpus endometrial carcinoma with a primary diagnosis of "mutation". "Amplification" was the predominant type of CNA in uterine carcinosarcomas, which has a prevalence of ~ 2% (Fig. 3A). A copy number deletion of LSD1 was noted in cholangiocarcinoma patients with genetic alteration (~ 3% frequency) (Fig. 3A). Figure 3B shows the 3D structure of LSD1 protein. Figure 3C shows the types, sites, and number of LSD1 genetic changes. We noticed the most frequent alteration was the E477K modification in the amino_oxidase of LSD1.

Phosphorylation analysis data of proteins

A comparison of LSD1 phosphorylation levels between normal tissues and primary tumor tissues was also performed in our study. The CPTAC dataset was used to analyze six types of tumors (breast carcinoma, UCEC, clear cell RCC, ovarian carcinoma, colon carcinoma, and LUAD). In all primary tumor tissues, the S166 locus of LSD1 shows differentially expressed phosphorylation levels in comparison to normal tissues (Fig. 4A-F, all P < 0.05), followed by a differentially expressed phosphorylation level of the S69, S131, S131S137, S131Y135, S137, S849, Y135S137, Y135Y136 and Y136 locus for breast cancer (Fig. 4A, P < 0.05), the S131, S137, S855, Y135 locus for UCEC (Fig. 4B, P < 0.05), the S131, S131Y135 locus for clear cell RCC (Fig. 4C, P < 0.05), the S131, S131Y135 locus for clear cell RCC (Fig. 4C, P < 0.05), the S69, S131 locus for colon cancer (Fig. 4E, P < 0.05) and the S131, S131Y135 locus for LUAD (Fig. 4F, P < 0.05).

Analysis of immune infiltration data

Tumor-infiltrating immune cells are prominent components of the tumor microenvironment and are closely linked to the initiation, progress, and metastasis of cancer. The results showed that various tumor-infiltrating immune cells were modulated by cancer-associated fibroblasts in the stroma of the tumor microenvironment. In this study, the TIMER, CIBERSORT, CIBERSORT-ABS, QUANTISEQ, XCELL, MCPCOUNTER and EPIC algorithms were used to investigate the potential association between immune cell infiltration levels and LSD1 gene expression in diverse carcinoma types of the TCGA. After a series of analyses, we concluded that cancer-associated fibroblast_TIDE infiltration and LSD1 expression were statistical positively correlated in BRCA-LumA, ESCA, KIRC, PAAD and PCPG tumors, and statistical negatively correlated in THYM tumors (Fig. 5). In addition, we found a statistically significant relationship between LSD1 expression and the approximated infiltration value of cancer-associated fibroblasts_EPIC in TCGA tumors from CESC, HNSC, HNSC-HPV-, LUAD and LUSC (Fig. 5).

Analyse of partners associated with LSD1

We tried to look for LSD1-binding proteins and the expression-related genes of LSD1 for a series of enrichment analyses of the signal pathways to investigate the molecular and cellular mechanisms of LSD1 involvement in tumor development. By using the STRING tool, we identified 51 LSD1-binding proteins with experimental support. Figure 6A shows the interaction network of these proteins. Figure 6B showed that LSD1 expression levels were positively correlated with those of the DHX9 (R = 0.58), HNRNPR (R = 0.63), MRTO4 (R = 0.59), RCC2 (R = 0.59) and SNRNP40 (R = 0.59) genes (all P < 0.001). In addition, the heatmap data showed a positive correlation between LSD1 and the above five genes in most cancer types (Fig. 6C). The two datasets were combined to conduct KEGG and GO enrichment analyses. The KEGG results indicated that “RNA Transport”, “mRNA Surveillance Pathway” and “spliceosome” could all play a role in the effect of LSD1 on tumor pathogenesis (Fig. 6D). As shown in Fig. 6E, the GO enrichment analysis further showed that most of these genes are related to RNA metabolism or pathways, such as mRNA splicing (via spliceosome), RNA splicing, mRNA 3’-UTR binding, RNA transport, and Mrna surveillance pathway.

LSD1 is known to participate in many cells biological processes across many species, such as RNA splicing, mRNA splicing, and spliceosome formation [28–31]. Based on the "HomoloGene" and phylogenetic tree analysis, it was found that the LSD1 protein structure was conserved across species, which indicates that similar molecular mechanisms may exist for the normal physiological role of LSD1 in our study. A growing number of studies have found a functional relationship between LSD1 and clinical diseases, especially tumors [32–34]. Further research is needed to determine if LSD1 is involved in the pathogenesis of various tumor types through certain common mechanisms. As far as we know, we failed to find any publications discussing an LSD1 pan-cancer analysis in the way of overall cancers. Consequently, on the basis of the data from TCGA, CPTAC and GEO databases, and the molecular features of gene expression, genetic alteration, DNA methylation, or protein phosphorylation, we examined LSD1 gene expression in 33 different cancer types.

Compared to adjacent normal tissues, most tumors express LSD1 more highly. However, the survival prognosis analysis for LSD1 showed different conclusions for different kinds of tumors [35, 36]. The GEPIA2 tool was used in our study to investigate the relationship between the expression of LSD1 in tumors and poor overall survival prognosis. Using the cBioportal tool, we analyzed 30 tumor samples for mutations of LSD1 and assessed the phosphorylation level of LSD1 between normal tissue and tumor tissue using the CPTAC dataset.

Our study was the first to present evidence that LSD1 expression can be associated with MSI or TMB across all of the TCGA tumors. Moreover, by using the information on LSD1-binding components and LSD1 expression-related genes across all tumors, we performed enrichment analyses and elucidated the etiology and pathogenesis of tumors, we confirmed the potential influence of “RNA Transport”, “mRNA Surveillance Pathway” and “spliceosome”. By using various immune deconvolution methods, we found there to be a negative correlation between LSD1 expression and immune infiltration levels in cancer-associated fibroblasts_TIDE, EPIC and in BRCA-LumA, ESCA, KIRC, PAAD, PCPG, THYM, CESC, HNSC, HNSC-HPV-, LUAD, LUSC tumors. In addition, our study showed that LSD1 expression is related to immune infiltration from cancer-associated fibroblasts in some tumors.

The CPTAC dataset enabled us to study the molecular mechanisms of the LSD1 protein in breast carcinoma, UCEC, clear cell RCC, ovarian carcinoma, colon carcinoma and LUAD with respect to total proteins and phosphoproteins. Results indicated that the expression level of LSD1 phosphorylation was different in primary tumors compared with normal tissues. To date, it has not been determined whether different phosphorylation levels of LSD1 of S166 are the result of dysregulated signaling in tumor cells. Therefore, it is necessary to explore the potential role of LSD1 phosphorylation at S166 and its potential regulation in tumor formation through further experiments

In conclusion, our first pan-cancer analysis of LSD1 suggested that in various tumors, LSD1 expression was statistically associated with clinical prognosis, DNA methylation, targeting proteins phosphorylation, immune cell infiltration, tumor mutation load or microsatellite instability. It is important to understand how LSD1 is involved in tumorigenesis in light of clinical tumor samples.

Ethical approval and consent to participate: Not applicable.

Consent for publication: Not applicable.

Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interest: The authors declare no conflict of interest.

Funding: This work was supported by grants from the Hospital Pharmacy Research Foundation of Guangdong Province (No. 2022A17) and the Traditional Chinese Medicine Scientific Research Project of Guangdong Province (No. 20221415). Authors' contribution: Ying-Ying Shao and Rui-Rong He conceived and designed the experiments; Ying-Ying Shao, Qiu-Hong Yang and Han-Bin Zhang performed the experiments and wrote the paper; Shu-Fen He, Yong-Xiang Xu and Shao-Bo Ding revised the entire paper; Bao-Cheng Xie and Wei-Chao Han analyzed the data. All authors approved the final version of this paper.

Acknowledgement: This work was supported by grants from the Hospital Pharmacy Research Foundation of Guangdong Province (No. 2022A17) and the Traditional Chinese Medicine Scientific Research Project of Guangdong Province (No. 20221415). This study was supported in part by resources and technical expertise from Central Laboratory of Southern Medical University Affiliated Dongguan Hospital.

Author Information: ^1.Department of Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, China. ^2.Zunyi Medical University, 563003, Zunyi, China.

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No competing interests reported.

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A pan-cancer study of the role of lysine specific demethylase 1 (LSD1) in human cancers

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Version 1

Abstract

Figures

Introduction

Materials And Methods

Gene expression analysis

Survival prognosis analysis

Genetic alteration analysis

Immune infiltration analysis

LSD1-related gene enrichment analysis

Results

Analysis of expression data for LSD1

Survival analysis data

Genetic alteration analysis data

Phosphorylation analysis data of proteins

Analysis of immune infiltration data

Analyse of partners associated with LSD1

Discussion

Declarations

References

Additional Declarations

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