In this study, we found a large number of epi-lncRNAs by using public databases such as TCGA, ENCODE and lncRNAs Transcripts, combined with the joint analysis of genomics, transcriptomics and epigenetic genomics. Many of these epi-lncRNAs have been reported to be associated with cancer in previous literature.
It can be clearly seen from our results that the rate of epi-lncRNA in prostate cancer (8.5%) is much lower than that of epi-PCG (50.2%) (Fig. 1), which is basically consistent with previous literature reports. Previous studies have shown that in specific tissues and cells, the overall occupancy of histone marks across lncRNA genes is in the range 27% - 38%, while that on the transcriptional start sites of protein-coding is 65%-73% . LncRNA transcription is generally regarded as a genome-wide monitoring mechanism and plays an important role in RNA quality control. The relatively low aberration rate of LncRNA in prostate cancer also indirectly reflects its high stability in the process of gene transcription or expression, which may be more suitable as a molecular marker of prostate cancer. In addition, from characterizing genomic signatures, it is also observed that epi-lncRNA had similar structural characteristics to epi-PCG except for the shorter length of transcripts. Compared with non-epi-lncRNA and non-epi-PCG, they have more transcripts, exons and longer exon length (Fig. 2). Based on the multiple relationships between epi-lncRNAs and PCGs (inter-gene, overlap, partial overlap, intron or exon) [23, 24], the more complex the splicing pattern of lncRNA is, the more likely it is to be regulated by abnormal epigenetic modification . Our results also coincide with the above view.
In the landscape of epi-lncRNA, it is not difficult to find that H3K4me3, H3K4me1, H3K27ac and H3K27me3 account for a high proportion of abnormally modified histones in the causes of lncRNA epigenetic disorders, and these abnormally modified histones are mainly concentrated in the promoter region (Fig. 2). Combined with the ssGSEA analysis of epi-lncRNAs (Fig. 3), we further found that the abnormal expression of H3K4me3, H3K4me1, H3K27ac and H3K27me3, whether located in the enhancer or promoter region, they almost consistently showed protective effects. H3K9me3_enhancer, H3K36me3_enhancer and H3K36me3_promoter showed significant cancer promoting effect. Although the latter accounts for only a small proportion in the epi-lncRNA genome landscape, it eventually leads to tumorigenesis. It shows that abnormal modification of H3K36me3 plays an extremely important role in the development of prostate cancer. This seems to reflect a message that under the gene expression pattern of prostate cancer, the final outcome of epigenetic aberrant regulation does not depend on the number of histone aberrant modifications. On the contrary, the type, location or function of histone aberrant modification may be more important. Inhibition of abnormal modification of H3K36me3 may bring new hope for the treatment of prostate cancer.
We analyzed 39 KEGG pathways most related to 12 kinds of epi-lncRNA and found that different types of epi-lncRNA-related pathways had certain consistency and included a large number of metabolism-related pathways (HISTIDINE_METABOLISM, TYROSINE_METABOLISM, BETA_ALANINE_METABOLISM, PHENYLALANINE_METABOLISM) and tumor-related pathways (COLORECTAL_CANCER, ENDOMETRIAL_CANCER, PROSTATE_CANCER). Thus, it can be seen that epigenetic abnormal LncRNA affects the biological specific molecular function of prostate cancer by changing the abnormal modification of histone and plays an important role in the pathogenesis of prostate cancer.
Previously, RNA modification was not considered to be a cancer driver, but accumulated evidence gradually suggests that abnormal RNA modification contributes to cancer cell proliferation, self-renewal, migration, stress adaptation and survival, and was named epitranscriptome in 2015. The functional study of these modifications is now on the rise and has shown great significance in human pathology [27, 28]. We visualized the correlation between 12 categories of epi-lncRNA enrichment scores and M6A, M5C and M1A modified genes. Among them, enhancer and promoter of H3K9me3, H3K27me3, H3K27ac, H3K4me1 and H3K4me3 have both similar and unique correlations with these genes. This suggests that there may be different regulation modes of lncRNA disorders caused by histone modification in enhancer and promoter, and these epi-lncRNAs are closely related to RNA modification. These results have confirmed previous findings. These findings [29–31] emphasize that DNA, RNA and histone and their modification work together in a synergistic manner, leading to a special chromatin state that determines the important function and ultimate direction of the genome. m6A is an important post-transcriptional regulation mechanism of genes [32–34]. It is also the most abundant and well-characterized internal modification in mRNA. It plays an important role in a variety of normal and pathobiological processes, including the regulation of self-renewal of embryonic stem cells and cancer cells, and survival after DNA damage [35–37] However, how N6-Methyladenosine m6A is accurately and dynamically deposited in the transcriptome has always been a mystery. Until a recent study found , H3K36me3 was regarded as a transcriptional extension marker that could guide m6A modification globally. M6A modification was enriched near the H3K36me3 peak. When intracellular H3K36me3 was exhausted, m6A modification decreased as a whole. H3K36me3 can be directly recognized and bound by RNA methyltransferase METTL14, promoting the binding of m6A-MTC to adjacent RNA polymerase II, thus transferring m6A-MTC to newly born RNA with active transcriptional activity, resulting in m6A co-transcriptional deposition. Our results further support the above findings.
One of the 14 prostate cancer epi-lncRNAs screened (HOXA11-AS) was not only related to the histone modified promoter but also related to the DMR promoter. The remaining 13 related epi-lncRNAs (GLIDR, LINC00308, PCAT14, PCAT18, PCAT5, SNHG12, SNHG17, SNHG6, MPo -AS1, HOTTIP, LINC00663, LINC00844, MIR222HG) was only associated with histone modified promoters. These results were consistent with our previous findings in the landscape of epigenetic-dysregulated lncRNAs of prostate cancer, that is, the areas with abnormal histone modification were mainly concentrated in the promoter region (Fig. 3B). By comparing the performance of the 14 genes on the TCGA dataset, 78.57% of them were consistent with those in the Lnc2Cancerv3.0 database, which once again verified the reliability of the research results.
We identified three lncRNAs (HAR1A, SNHG12, SNHG17) to construct the prostate cancer 3-EpiLncRNA signature. These three lncRNAs are independent prognostic markers of prostate cancer and have been identified as risk factors for a variety of cancers. HAR1A, also known as LINC00064, is widely expressed in brain, testis, spleen, lymph nodes and prostate tissues. Previous studies have shown that HAR1 is related to the development and evolution of the brain [39, 40]. A recent study suggests that HAR1 is also associated with tumorigenesis, regulating the progression of oral cancer through α-kinase-1, bromodomain-7 and myosin IIA axis.SNHG12 is usually overexpressed in tumor cells and may promote tumorigenesis and metastasis by acting as a sponge of microRNA[42, 43]. There is evidence that SNHG12 promotes prostate tumorigenesis and progression through AKT regulation , and promotes renal cell carcinoma progression and resistance to sunitinib through up-regulation of CDCA3. LncRNASNHG17 is a non-coding RNA widely expressed in human body, with the highest expression in bone marrow, followed by high expression in ovary, prostate, thyroid and other organs, which is closely related to the progression of osteosarcoma  and promotes the proliferation of gastric and colon cancer cells through epigenetic silencing of P57[47–49]. In order to evaluate the predictive value of the model, we visualize the model and draw the survival curve and ROC curve (Fig. 8). The high 3-EpiLncRNA score of prostate cancer began to show a significant survival disadvantage in the fifth year, and the number of survivors in the 10th year was only 1/3 of the low 3-EpiLncRNA score. ROC analysis showed that the 1-year AUC, 3-year AUC and 5-year AUC of 3-EpiLncRNA signature were 1, 0.78 and 0.79, respectively, indicating that the model has a good ability to evaluate the prognosis and can be used to predict the survival of prostate cancer.
In summary, our study analyzed the relationship between abnormal expression of lncRNA and epigenetic disorders and related genomic characteristics, and screened three specific epi-lncRNA for the construction of prostate cancer prognosis-related models. Mining data from a new perspective and supporting previous experimental research. At the same time, it is also found that the abnormal expression of LncRNA caused by the abnormal modification of enhancer-related H3K36me3 may be an important factor in the occurrence of prostate cancer. Reversing the abnormal modification of H3K36me3 may provide a new way for the treatment of prostate cancer, but further experimental research is needed.
At present, unexpected progress has been made in the analysis of the molecular mechanism of epigenetic regulation, which has a far-reaching impact on a better understanding of normal development and the treatment of human diseases. Different from genetic changes, the errors in epigenetic characteristics will be reversible, which has important guiding significance for disease treatment and drug research. With the deepening of epigenetic and other multi-group studies, the veil of prostate cancer will be lifted layer by layer, and it is expected to achieve an important breakthrough in future research.