Long non-coding RNAs (lncRNAs) are transcribed by RNA polymerase II and range in length from 200 nucleotides to 100 kilobases without coding for proteins (1); ~95% of the human genome consists of nc sequences that are transcribed into lncRNAs (2). These lncRNAs can be classified into long intergenic nc (linc), enhancer, intronic and antisense lncRNAs (3). Additionally, lncRNAs modulate gene expression involved in multiple biological processes, including cell apoptosis, proliferation and differentiation and post-transcriptional, translational and epigenetic regulation (4,5).

lncRNAs play important roles in regulating chromatin structure and oncogene expression, thereby contributing to tumorigenesis (6). Mechanistically, lncRNAs directly recruit epigenetic and/or epitranscriptomic regulators to control oncogene expression, driving tumor development and progression (7). Rapid advancements in genome-wide technologies are accelerating identification of novel lncRNAs and their regulatory mechanisms in carcinogenesis. Notably, lncRNAs are involved in epigenetic regulation by modifying chromatin structures (primarily acetylation and methylation) through specific enzymes, including DNA- and histone-modifying enzymes, and chromatin organization-associated proteins (8). Furthermore, lncRNAs are essential for modulating the three-dimensional (3D) genomic architecture (9). CCCTC binding factor (CTCF), regulated by lncRNAs, serves as a master regulator of mammalian chromatin topologically associated domain (TAD) (10). CTCF controls oncogene expression by mediating chromatin TAD architecture and enhancer-promoter contacts within TADs (11). CTCF contains RNA-binding regions (RBRs) within its zinc finger (ZF) domains recognized by lncRNAs, which are key for CTCF self-clustering and CTCF-mediated long-range chromatin interaction (12,13). Deletion of RBRs notably disrupts half of CTCF mediated chromatin loops to cause deregulation of gene expression (12). lncRNAs cooperate with CTCF to mediate genome topological regulation, thereby leading to carcinogenesis (9). lncRNAs also regulate oncogene expression and carcinogenesis by recruitment of epitranscriptomic regulators, including RNA-modifying enzymes mediating RNA N6-methyladenosine (m⁶A) modification and RNA adenosine-to-inosine (A-to-I) editing (14). Thus, future studies may elucidate the interlocking functions of lncRNAs with both epigenome and epitranscriptome to develop novel cancer therapies and improve prognostic strategies (15).

Understanding the epigenetic and epitranscriptomic regulatory roles of lncRNAs in carcinogenesis is key for unraveling the molecular mechanisms underlying cancer development and progression. The present review aims to provide a comprehensive overview of how lncRNAs influence gene expression in carcinogenesis and their potential as diagnostic markers and therapeutic targets in oncology.

lncRNAs play key roles in mediating DNA modification, histone modification and chromatin organization to regulate oncogene expression in cancers. lncRNAs recruit DNA- and histone-modifying enzymes and chromatin organization-associated proteins at specific genomic loci to modulate gene expression in carcinogenesis (5,7,16-18).

RNA modifications, including methylation and RNA editing, are key for various cellular processes in cancer cells, including RNA stability, structure and metabolism, localization and translation (109). lncRNAs play key roles in carcinogenesis by recruiting RNA modification complexes at the specific gene loci. lncRNAs directly interact with RNA modification complexes, such as RNA methyltransferases and editing enzymes, to modulate RNA modification and gene expression in cancer genomes (Fig. 4A) (110-116). By serving as molecular guides or scaffolds, lncRNAs directly recruit RNA modifiers to target RNAs, thereby influencing RNA modification patterns and driving cancer progression.

lncRNA HIF1A-AS2 directly recruits the ADAR (adenosine deaminase RNA specific) enzyme to facilitate ADAR1-dependent A-to-I editing, driving breast cancer progression and metastasis (117,118). Similarly, lncRNA prostate cancer antigen 3 (PCA3) binds to ADAR enzyme, promoting A-to-I editing of PRUNE2 pre-mRNA and regulating expression of the tumor suppressor gene PRUNE2, thereby contributing to the development of prostate cancer (119) (Fig. 4B). Additionally, the expression of lncRNA LINC00944 is associated with ADAR1 levels and mediates ADAR interactions with Dicer or Staufen protein, linked to poor survival in breast cancer (110). Consequently, lncRNAs impact expression of their target RNAs and contribute to tumorigenesis by interacting with the RNA A-to-I editing modifier ADAR (Table SI).

lncRNA MALAT1 recruits methyltransferase-like 3 (METTL3) to induce m⁶A modification of miR-26b, promoting epithelial-mesenchymal transition and metastasis via the MALAT1/miR-26b/HMGA2 (high mobility group AT-hook 2 (HMGA2) axis in breast cancer (120,121). Additionally, lncRNA AI662270 enhances CTGF (Connective tissue growth factor) expression post-transcriptionally by recruiting METTL3 to the CTGF promoter and inducing m⁶A modifications on the nascent mRNA in carcinogenesis (111). Moreover, lncRNA ARHGAP5-AS1 recruits the METTL3 enzyme to mediate m⁶A methylation of ARHGAP5, thereby stabilizing this gene in the cytoplasm and conferring chemo-resistance in gastric cancer (115) (Fig. 4C). Another oncogenic lncRNA, LNC942, interacts with the METTL14 enzyme to stabilize downstream oncogene expression, promoting cancer cell proliferation and progression (122).

Recent studies have revealed interactions between lncRNAs and m⁶A recognition proteins, such as YTHDC1 (YTH domain containing 1) (123), YTHDF2 (YTH Domain Family 2) (124) and ALKBH5(AlkB Homolog 5) (113), regulate cellular processes associated with cancer development. For example, lncRNA HCG11 recruits m⁶A recognition protein IGF2BP2 (IGF2 mRNA binding protein 2) to stabilize LATS1 (Large tumor suppressor homolog 1) mRNA, enhancing LATS1 expression in lung adenocarcinoma (116) (Fig. 4D). lncRNA MALAT1 interacts with m⁶A recognition protein YTHDC1 to regulate nuclear speckle composition and oncogene expression in carcinogenesis (125). lncRNA-CBSLR recruits m⁶A recognition protein YTHDF2 to form the CBSLR (CBS MRNA Stabilizing LncRNA)/YTHDF2/CBS (cystathionine-beta-synthase) complex which decreases CBS mRNA stability in an m⁶A modification-dependent manner in gastric cancer (126). lncRNA lncNRON recruits the m⁶A eraser ALKHB5 demethylase to decrease Nanog m⁶A methylation, inhibiting Nanog mRNA decay in gastric cancer (127). Additionally, anti-sense lncRNA FOXM1-AS recruits the m⁶A eraser ALKBH5 to decrease m⁶A abundance on sense mRNA, leading to activation of downstream targets in glioblastoma stem-like cells (128). Moreover, studies have demonstrated lncRNA KB-1980E6.3, associated with hypoxia, recruits the m⁶A reader IGF2BP1 to stabilize c-Myc mRNA, thereby maintaining breast cancer stem cell stemness (129,130) (Fig. 4A-D; Table SI).

In summary, studies have highlighted the role of lncRNAs in mediating epitranscriptomic modifications, which are reversible chemical modifications on RNA molecules that impact oncogene expression and carcinogenesis (15,131,132). The interplay between lncRNAs and epitranscriptomic modification regulators in carcinogenesis underscores the complexity of regulatory networks that control oncogene expression in cancer (15). Some specific lncRNAs, such as MALAT1, ARHGAP5-AS1 and lncNRON, have been implicated in carcinogenesis by recruiting METTL3/METTL14 or ALKBH5 enzymes. Additionally, lncRNAs such as HCG11, lncRNA-CBSLR and KB-1980E6.3 regulate oncogene expression by recruitment of m⁶A readers. lncRNAs play a direct role in recruiting RNA modification complexes, including RNA methyltransferases and RNA editing complexes, to regulate RNA modifications and abnormal oncogene expression, ultimately contributing to carcinogenesis (Figs. 1-4; Table SI). Collectively, these findings underscore the diverse and complex regulatory roles that lncRNAs serve in mediating m⁶A modification and gene expression in various types of cancer, highlighting their potential as therapeutic targets for cancer treatment.

lncRNAs are key regulators of cancer biology, operating through both epigenetic and epitranscriptomic mechanisms (17,133,134). As epigenetic regulators, lncRNAs interact with chromatin-modifying complexes (such as polycomb repressors and DNA methyltransferases) to silence tumor suppressor genes or activate oncogenes (131,135). In their epitranscriptomic capacity, lncRNAs orchestrate RNA modification (such as m⁶A methylation and A-to-I editing) to stabilize oncogenic transcripts or enhance their translational efficiency (132). These dual regulatory roles establish lncRNAs as master regulators of cancer hallmarks, including proliferation, metastasis and therapy resistance. Beyond their mechanistic roles, lncRNAs are as critical diagnostic and prognostic biomarkers in carcinogenesis. Their tissue- and cancer-specific expression profiles, combined with their ability to regulate key oncogenic pathways (such as those controlling proliferation, apoptosis and metastasis), position them as promising tools for early cancer detection, risk stratification and personalized therapeutic strategies (136).

Advancements in transcriptome sequencing data availability may facilitate the discovery of lncRNA biomarkers. HOX family genes, such as HOTAIR, HOXBLINC and HOTTIP, are frequently upregulated in cancer and closely linked to carcinogenesis (18,59,61,92). Utilizing HOTAIR measurement for risk stratification of patients undergoing surgery may enhance precision medicine strategies for aggressive esophageal cancer (27). Mechanistically, HOTAIR influences the expression of the MTHFR gene by recruiting DNMT3s to the MTHFR gene promoter, resulting in esophageal cancer chemoresistance (27) (Fig. 1B). The function of HOTAIR lncRNA may be context- or cell-type-specific, but it still serves as a valuable clinical prognostic indicator. In patients with metastatic AML, high levels of HOTTIP expression are associated with shorter overall survival and increased responsiveness to WNT inhibitor ICG-001 treatment compared with those with low levels (18). Mechanistically, HOTTIP regulates HOXA9 oncogene expression and the WNT/β-Catenin signaling pathway, influencing AML development and progression (18) (Fig. 2B). In addition, HOTTIP coordinates with CTCF in mediating R-loops and TAD formation at crucial hematopoietic/leukemogenic loci to regulate expression of leukemia-related genes in AML leukemogenesis (91) (Fig. 3B). HOXBLINC expression is associated with poor prognosis in AML based on The Cancer Genome Atlas datasets (50) (Fig. 2C). HOXBLINC shows the highest levels of elevated expression in patients with AML with disease progression compared with patients without progression, suggesting its potential as a reliable biomarker with cancer- or tissue-specific expression profiles in AML.

Aberrant expression of lncRNAs and their involvement in cellular processes establish them as promising therapeutic targets for cancer. Studies have highlighted the importance of elucidating lncRNA-mediated mechanisms in cancer development and metastasis (59,77,125,137). For example, inhibitors targeting LINC01212 have efficacy in melanoma treatment (138). lncMyoD has been identified as a functional regulator of IMP1 (IGF2 mRNA-binding protein (IMP)1 and IMP2, highlighting its therapeutic potential in sarcoma (139). Additionally, lncRNA-6585 and its associated antibody are under investigation for cervical cancer diagnosis and therapy (138). Emerging strategies, such as nanomaterials-based technologies, represent cutting-edge approaches for targeting lncRNAs in cancer therapy (140). These innovations, including nanoparticle delivery systems, enhance specificity and efficacy of RNA-based therapies (140). A recent study systematically summarized advances in targeting the lncRNA-Wnt axis with flavonoids for colorectal cancer (CRC) therapy, underscoring the potential of flavonoid-based strategies to exploit epigenetic mechanisms for CRC prevention and treatment (141).

lncRNAs are increasingly leveraged in nucleic acid-based therapeutics in cancer, including CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeats associated protein 9) sgRNA design, small interfering RNA (siRNA) and antisense oligonucleotides (ASOs) (142). For example, CRISPR/Cas9 sgRNA-mediated silencing of UCA1, NEAT1 or MALAT1 inhibits cancer cell metastasis (70,143). MALAT1 serves as a druggable lncRNA for precision anti-cancer strategies, while microRNAs and lncRNAs represent promising targets in drug development (70,144). Furthermore, siRNA and ASOs enable precise gene silencing, making them key tools for research and clinical applications (143,144). For example, siRNA targeting DDX11 antisense RNA 1) has been developed for liver cancer therapy (145). In a luminal mouse mammary tumor virus-PyMT mouse mammary carcinoma model, promoter depletion or ASO-mediated knockdown of MALAT1 notably decreases lung cancer metastasis (120).

Collectively, lncRNAs are associated with cancer development and progression, underscoring their potential as prognostic and predictive biomarkers. Their cancer- or tissue-specific expression profiles across malignancies highlight their clinical relevance. The integration of lncRNAs into clinical oncology signifies a new era of precision medicine. Their dual use as diagnostic/prognostic markers and therapeutic targets may transform cancer management by enabling earlier detection, personalized treatment and dynamic monitoring. As research advances, lncRNAs are poised to transition from experimental discoveries to key assets in treating cancer, offering now avenues for improving patient outcomes.

The aberrant expression of lncRNAs is associated with poor prognosis of patients with cancer. Understanding the mechanisms by which lncRNAs drive cancer progression is key for developing effective therapy (146). lncRNAs possess structural versatility, enabling them to recruit epigenetic and epitranscriptomic regulators, including PRC1, PRC2, LSD1, MLL, DNMTs, CTCF, cohesin, METTL3 and ALKBH5. By interacting with these regulators, lncRNAs modulate the epigenome and amplify oncogenic pathways in carcinogenesis (147,148). Therefore, future studies may elucidate the interlocking functions of lncRNAs with epigenetic or epitranscriptomic regulators to develop new cancer therapies and earlier prognosis strategies (46).

Dysregulation of lncRNA-mediated DNA modification is implicated in tumor initiation, progression and metastasis (27). Understanding crosstalk between lncRNAs and DNA modification in cancer is crucial for investigating underlying molecular mechanisms of tumorigenesis. Aberrant DNA 5mC methylation patterns, such as hypermethylation of tumor suppressor genes and hypomethylation of oncogenes, are implicated in cancer development and progression. lncRNAs recruit DNMTs complex to the specific genomic loci, leading to changes in DNA methylation patterns and oncogene expression during carcinogenesis (26,27). For example, lncRNA HOTAIR recruits DNMT3A/3B complex to the promoter regions of tumor suppressor gene MTHFR, promoting cancer cell proliferation and metastasis (27). Moreover, HOTAIR epigenetically suppresses the miR-122 expression via DNMTs-mediated DNA methylation, contributing to hepatocarcinogenesis (149). Additionally, lncRNAs, such as HAGLR, CCDC26 and TTTY15, have been implicated in recruiting DNMTs to influence the DNA methylation of their targets in cancer cells (33-35). Overall, recruitment of DNMTs by lncRNAs represents the epigenetic mechanism by which lncRNAs regulate oncogene expression in carcinogenesis (Fig. 1A-D). Although numerous lncRNAs can influence the DNA methylation of their targets leading to carcinogenesis, it is unknown which regulators are recruited by lncRNA in cancer. Further studies should explore the epigenetic mechanisms of lncRNA-mediated DNA modification in cancer genome.

The recruitment of histone modification complexes by lncRNAs serves a crucial role in the regulation of gene expression patterns associated with cancer development and progression. lncRNAs recruit HAT complexes to specific genomic loci, resulting in changes in histone acetylation patterns during carcinogenesis (59,60). This recruitment of histone modifying regulators by lncRNAs regulates changes in gene expression patterns associated with cancer cell proliferation, invasion, metastasis, apoptosis, cell cycle progression and drug resistance (Fig. 5). For example, lncRNA HOTAIR interacts with the HAT complex PRC2 to increase H3K27me3 at oncogene promoters and subsequently silence their expression (59-61) (Fig. 2A-B). Additionally, HOTAIR and Air interact with PRC2 complex or G9a to regulate histone acetylation or methylation at specific gene loci, promoting tumorigenesis (51,59-61). Furthermore, oncogenic lncRNAs HOTTIP, HOXBLINC, MIAT, LAMP5-AS1, ANRIL, CircAGFG1, PANDA and LINP1, directly interact with MLL, DOT1L, SETD1A and EZH2, influencing cancer cell proliferation, cell cycle progression and apoptosis (Fig. 5). lncRNA AGAP2-AS1 directly binds CBP/P300 to mediate the H3K27 acetylation at the promoter of the carcinogenic protein MyD88, leading to chemoresistance in breast cancer (82) (Figs. 2D and 5). While the role of lncRNA-mediated histone modification in carcinogenesis is well-established (18,50,51,53,55,69), further research is needed to understand how lncRNAs recruit histone modification complexes. The present review provides an overview of the current understanding of how lncRNAs mediate the recruitment of histone modification complexes in carcinogenesis, emphasizing the potential of targeting lncRNA-histone modifier interactions as a therapeutic approach for cancer treatment (Fig. 5).

RNA modifications, such as m6A methylation and A-to-I editing, influence mRNA stability, translation and splicing. Dysregulation of m6A methylation is implicated in various cancers. lncRNAs recruit the METTL3/METTL14 complex to mediate m6A methylation, regulating target gene expression and driving tumor growth and metastasis (150,151). lncRNA MALAT1 recruits the METTL3/METTL14 complex to promote methylation and subsequent translation at specific mRNAs, enhancing NSCLC cell proliferation and invasion (112). lncRNAs recruit m⁶A readers and eraser to mediate oncogene expression or inactivate tumor suppressive genes in carcinogenesis, such as IGF2BP1, IGF2BP2, YTHDC1, YTHDF2 and ALKBH5 (116,125,126,128,129). Additionally, ADAR1-dependent A-to-I editing serves a critical role in the progression and metastasis of cancers (117,118). lncRNAs PCA3 and LINC00944 recruit ADAR to regulate the expression of the tumor-related genes in carcinogenesis (110,119) (Fig. 4A-D). Overall, the recruitment of the RNA A-to-I editing enzyme, METTL3/METTL14 complex and m⁶A or m⁶A readers by lncRNAs represents a novel epitranscriptomic mechanism by which lncRNAs modulate oncogene expression driving carcinogenesis.

In addition, lncRNAs serve essential roles in 3D chromatin organization by recruiting, bridging, and guiding the CTCF/cohesin complex to specific genomic regions. Depletion of RBRs disrupts CTCF-mediated DNA recognition and binding and chromatin loops in cancer genome (12). Thus, lncRNAs coordinate with CTCF, contributing to the genome topological regulation via the RNA-dependent mechanism. lncRNA HOTTIP coordinates with CTCF to mediate TAD formation at key hematopoietic/leukemogenic loci for AML development and progression (18) (Fig. 3B). lncRNA HOTTIP also cooperates with CTCF/cohesin-mediated TAD structure in LSC regulation and AML leukemogenesis according to its function in specific leukemic genome topology (91) (Fig. 3B). These findings suggest that lncRNAs contribute to genome topological regulation via RNA-dependent mechanisms. Further research is needed to explore the roles of architectural RNAs and regulatory lncRNAs in CTCF/cohesin-mediated chromatin organization across numerous types of cancer.

lncRNAs serve physiological and pathological roles in numerous aspects of genome function and biological processes, such as cell development, differentiation, proliferation, invasion and migration. Unlike protein-coding genes, lncRNAs lack well-defined domains, making their regulatory mechanisms diverse and complex (152). Notably, lncRNAs >300 bp contain multiple functional domains that interact with various factors to coordinate activity in both time and space (153). For example, HOTTIP cooperates with WDR5/MLL/DOT1L, a large family of RNA-binding proteins involved in cellular processes such as alternative splicing, mRNA stability and transcriptional regulation (18). Furthermore, HOTTIP can bind to the RNA binding domains of CTCF/cohesin, leading to aberrant induction of oncogene expression and the WNT pathway in leukemogenesis (91). lncRNA HOTTIP mediates histone modification and chromatin organization to regulate HOXA oncogene expression and WNT signaling pathways by recruiting modifiers, including WDR5/MLL/DOT1L and CTCF/cohesin. The 3,343 bp lncRNA HOTTIP contains different functional domains that can recruit different DNA or RNA modifying regulators. Experimental frameworks for studying the cis- and trans-acting functions of this lncRNA have been detailed in previous research (18,91). Similarly, upregulation of MALAT1 lncRNA in various types of cancer, along with its pleiotropic roles in gene regulation, has made it a target for therapeutic interventions in cancer (70). lncRNA MALAT1 suppresses E-cadherin expression, promoting OS metastasis by recruitment of the PRC2 member EZH2 (69). lncRNA MALAT1 also plays a key role in chromatin remodeling to promote inflammation-associated hepatocellular carcinoma progression by interaction with BRG1 (101,102). Additionally, MALAT1 regulates the expression of miR-26b by recruiting METTL3, leading to the invasive and metastatic behavior of breast cancer via the MALAT1/miR-26b/HMGA2 axis (120,121). These examples illustrate how lncRNAs with multiple functional domains interact with diverse modifiers to regulate cancer progression. While experimental studies have provided insight into lncRNA functions, further research is needed to clarify their regulatory mechanisms across numerous types of cancer.

Previous studies have challenged traditional views of lncRNA function, highlighting their key roles in cancer development (154,155). Advances in RNA-associated technologies, such as ChIRP-seq (chromatin isolation by RNA purification sequencing), ChIRP-Mass Spectrometry), and iDRiP (identification of direct RNA interacting proteins), have enabled identification of lncRNAs that interact with DNA-modifying enzymes, histone modifiers, RNA-modifying complexes and chromatin-organizing proteins (156-158). Moreover, a deep understanding of lncRNA-driven epigenetic and epitranscriptomic regulation through next-generation sequencing technology strengthen its association with carcinogenesis (84). The regulation of lncRNAs in human may lead to the discovery of promising targets for cancer therapeutics. This has spurred the rapid growth of epigenetic drug discovery, with drug-targeting epigenetic enzymes being tested in the clinic for the treatment of various types of human cancer (159-161). lncRNAs provide a platform for identifying epigenetic targets, enabling the development of epi-drugs to counteract aberrant epigenetic enzymes. lncRNA expression shows high specificity, as they are expressed at different developmental stages and in a cancer type-specific manner (162,163). Disrupting expression of a specific lncRNA associated with epigenetic regulation can lead to the upregulation of its target (6).

Understanding of how lncRNAs mediate epigenetic and epitranscritomic regulators to control the cancer biological processes, such as invasion-metastasis, and influence the tumor microenvironment is steadily advancing (Fig. 5; Table SI). Critically, lncRNAs form relatively stable secondary and higher structures to facilitate cellular organization and gene regulation, including DNA replication, RNA transcription, protein translation and cell and cell differentiation (164,165). The complex structural features make lncRNAs potential players in epigenetic regulation in various types of cancer (96). Multiple pieces of evidence suggest that structural features of lncRNAs are essential for understanding their function and roles in cancer development and progression (7,15,29,33,69). In conclusion, the present review highlighted the role of lncRNA in mediating epigenetic and epitranscriptomic regulation to control oncogene expression. Directly recruiting DNA modifying complex, histone modifying regulators, chromatin organization associated regulators, and RNA modifying complex plays a role in carcinogenesis. Understanding lncRNA functions and structures is key for developing targeted cancer therapy.