Open research questions in Cancer-related gene regulation

What the literature leaves open

• Future research should focus on strategies that modulate these cofactors — or their downstream effectors — to generate new therapeutic approaches that leverage their dual role in neurogenesis and tumor suppression. iii) To outline the key areas where evidence is lacking and suggest specific directions for future research, we should mention: i) the gene domain-specific causality in vivo; ii) the deadenylation specificity; the rules the apoptosis decision map, underlying the anti-apoptotic and the pro-apoptotic activity of BTG2 and BTG1; iv) the BTG1’s role in MB, in particular concerning cancer stem cells.

  PC3/Tis21/BTG2 and BTG1 genes: regulators of the cell cycle and neurogenesis, as well as tumor suppressors in malignant brain tumors · 2026 · DOI

• A549-MRTXR cells exhibited a narrower resistance window than H838-MRTXR and H1437-MRTXR cells and were therefore not investigated further. Because genomic analysis in this study was limited to the PRMT5 coding region, future studies incorporating whole-genome sequencing, transcriptomic analysis, and epigenomic profiling will be required to define the genetic and non-genetic determinants of these resistance states. These findings demonstrate that MTAP loss alone is insufficient to predict MRTX1719 sensitivity, consistent with the modest ORRs observed clinically [43]. Thus, MTA availability can modulate the response to MRTX1719, but reduced MTA alone is insufficient to account fully for the acquired resistant phenotype.

  Acquired Resistance to the PRMT5 Inhibitor Confers Collateral Sensitivity to MEK Inhibition in MTAP-Null Non-Small Cell Lung Cancer · 2026 · DOI

• Whether YEATS2 regulation on NF-κB signaling pathway in ESCC involves histone acetylation, chromatin remodeling and gene transcription need to be further explored.

  YEATS2 promotes malignant phenotypes of esophageal squamous cell carcinoma via H3K27ac activated-IL6ST · 2025 · DOI

• Further in-depth research is warranted to fully elucidate the precise mechanisms through which PRMT5 activates the HIF1α pathway and to decipher the functional consequences of this activation.

  PRMT5 Mediated HIF1α Signaling and Ras-Related Nuclear Protein as Promising Biomarker in Hepatocellular Carcinoma · 2024 · DOI

• While previous studies have explored the role of PRMT5 in HCC, transcriptional activation of PRMT5 in HCC has not been examined. Further investigations into the specific interactions and downstream effects of PRMT5 in HCC development are warranted to fully comprehend its role and therapeutic implications in combating this aggressive form of cancer.

  PRMT5 Mediated HIF1α Signaling and Ras-Related Nuclear Protein as Promising Biomarker in Hepatocellular Carcinoma · 2024 · DOI

• Drug resistance is one of the major challenges of cancer treatment since it greatly limits the therapeutic options for the patient and worsens the prognosis. With the current push towards more personalised medicine, combining current chemotherapeutic regimens with specific PMT inhibitors could in the future be a strategy to ensure that a sub-set of patients can successfully benefit in the long-term from the treatment being administered. However, in order to achieve this there is a need for better understanding of the role of PKMTs and PRMTs in chemoresistance, through the collection of more comprehensive data from well-characterised patient cohorts. This is because most of the current published work on PMT inhibitors has focused on inhibiting enzymes which are dysregulated in relation to tumorigenesis and not chemoresistance, such that a more focused investigation is required in relation to whether chemoresistance can be reversed when administering such inhibitors and the identification of chemoresistance-specific targets. Despite being discovered years ago (Ambler and Rees, 1959), protein methylation has not been as widely studied as other PTMs due to the lack of confident identification, efficient enrichment strategies and experimental techniques (Deng et al., 2016; Levy, 2019; Micallef and Baron, 2023; Wang et al., 2017). In particular there needs to be a thorough understanding of the biological significance and role of non-histone proteins as substrates of PMTs in chemoresistance, which is still far from properly characterised. Technological advances in mass spectrometry for PTM identification as well as various methodological developments in the analysis of methyltransferase expression and activity will be required to obtain crucial information from clinical samples. Another important aspect to investigate is how PMTs are involved in the mechanism of the different chemotherapeutic drugs and lead to cancer cell evasion once dysregulated, which also requires the collection of much more evidence from different sources. The dysregulation of both PKMTs (such as EZH2, G9A, SETD7, SETD8, SYMD2 and SYMD3) and PRMTs (such as PRMT1, PRMT3, PRMT5 and PRMT6) in tumours has been shown to promote drug resistance in various ways such as by CSC renewal, activation of key signalling pathways like the Wnt/Notch pathway and through cell cycle progression. This would provide key mechanistic information and insight into how to design future inhibitors which would be specifically synergistic with selected chemotherapeutic drugs. Targeting PMTs strategically using small inhibitory molecules would aid in the reversal of drug resistance, thus promoting cell death within the evading cancer cells. Currently inhibitors are only available against a very small number of the known PMTs and the specificity and sensitivity of the available molecules are not always of the desired quality. In order to improve their efficacy, apart from developing more iterations of these inhibitory molecules, it would be ideal to design new inhibitory mechanisms. However, this option is somewhat limited considering that all PMTs use the same donor and mechanism to add methylation, and they fall within 2 families making their active sites particularly similar. Recently, the use of proteolysis-targeting chimera (PROTAC) or enzyme-substrate adaptor interaction inhibitors to inhibit methylation events mediate by PMTs have started to be implement against some PKMTs (Velez et al., 2023; Velez et al., 2024) and PRMTs (Martin et al., 2024;

  Therapeutic targeting potential of the protein lysine and arginine methyltransferases to reverse cancer chemoresistance · 2024 · DOI

• However, the mechanism by which it promotes tumor progression is still not fully understood.

  Targeting ENO1 reprograms macrophage polarization to trigger antitumor immunity and improves the therapeutic effect of radiotherapy · 2026 · DOI

• However, chemoresistance inevitable develops and the underlying mechanism remains poorly understood.

  PRMT5 upregulates KCNMB4 expression via histone methylation to promote paclitaxel resistance in advanced nasopharyngeal carcinoma · 2026 · DOI

• However, the PTMs of GLUD1, particularly arginine methylation, remain unexplored.

  AKT1 phosphorylates PRMT7 to promote GLUD1 methylation and gastric cancer progression · 2026 · DOI

• Euchromatic histone-lysine N-methyltransferase 2 (EHMT2) has been implicated in cardiovascular diseases, yet its role in vascular remodeling remains incompletely understood.

  EHMT2 aggravates vascular remodeling via epigenetic inhibition of GADD45G · 2026 · DOI

• Meningiomas are the most common primary brain tumors, yet the molecular pathways that distinguish grade 1 from grade 2 lesions remain insufficiently understood.

  Proteomic Analysis Identifies ATE1-Dependent Arginylation Dysregulation across Meningioma Grades · 2026 · DOI

• Among post-translational modifications, N-terminal arginylation─catalyzed by ATE1─regulates protein stability and cellular stress responses, but its role in meningioma biology has not been explored.

  Proteomic Analysis Identifies ATE1-Dependent Arginylation Dysregulation across Meningioma Grades · 2026 · DOI

• Background: Asthma involves chronic inflammation linked to metabolic reprogramming, but how metabolites reshape epigenetics through posttranslational modifications remains unclear.

  PCK2-Mediated PQBP1 Lactylation Promotes Asthmatic Inflammation through PRMT5 Inhibition · 2026 · DOI

• While PRMT5 is known to regulate multiple oncogenic pathways, including PI3K-AKT signaling, its role in lipid metabolism and ferroptosis, a regulated, iron-dependent cell death driven by lipid peroxidation, remains poorly understood.

  PRMT5 inhibition sensitizes B-cell lymphoma cells to ferroptosis · 2026 · DOI

• Nevertheless, the information on how Wnt ligands could mediate oral carcinogenesis in periodontitis remains scarce.

  Evaluating the link between periodontitis and oral squamous cell carcinoma through Wnt/β-catenin pathway: a critical review · 2025 · DOI

• However, a systematic synthesis of the multifaceted functions of PRMT1 across these diverse pathological contexts remains lacking.

  PRMT1 in Health and Disease: Emerging Perspectives From Molecular Mechanisms to Therapeutic Strategies · 2025 · DOI

• While the impact of TRIM21 on cancer has been studied in various tumors, its role in colorectal cancer (CRC) remains unclear.

  TRIM21-mediated PRMT1 degradation attenuates colorectal cancer malignant progression · 2025 · DOI

• However, the precise levels of expression, clinical significance, biological functions, and molecular mechanisms of CARM1 in HCC, particularly related to the downstream genes regulated by CARM1 through histone arginine methylation, remain unclear.

  PSMD14-mediated deubiquitination of CARM1 facilitates the proliferation and metastasis of hepatocellular carcinoma by inducing the transcriptional activation of FERMT1 · 2025 · DOI

• The coactivator-associated arginine methyltransferase 1 (CARM1) functions as an epigenetic writer, however, its role in mitosis remains poorly understood.

  CARM1 S217 phosphorylation by CDK1 in late G2 phase facilitates mitotic entry · 2025 · DOI

• The mechanism by which epithelial EpCAM-positive HCC cells transform into mesenchymal CD90-positive HCC cells remains unclear.

  Transcription factor JUNB is required for transformation of EpCAM-positive hepatocellular carcinoma (HCC) cells into CD90-positive HCC cells in vitro · 2025 · DOI

• Histone lysine succinylation, an emerging epigenetic marker, has been implicated in diverse cellular functions, yet its role in cancer drug resistance is not well understood.

  KLF6-mediated recruitment of the p300 complex enhances H3K23su and cooperatively upregulates SEMA3C with FOSL2 to drive 5-FU resistance in colon cancer cells · 2025 · DOI

• Active endoscopic surveillance has shown promise as an alternative management strategy for gastrectomy in patients lacking indicators of >T1a SRCC, though current data are limited by short follow-up periods and selection bias.

  Advancing the Evaluation and Management of CDH1-Associated Gastric Cancer · 2025 · DOI

• [4] However, information on the function of RNF115 in hepatocellular carcinoma remains unclear.

  RNF115 deficiency upregulates autophagy and inhibits hepatocellular carcinoma growth · 2025 · DOI

• However, the specific role of PRMT1 in lung metastasis and chemoresistance remains unclear.

  PRMT1-Mediated PARP1 Methylation Drives Lung Metastasis and Chemoresistance via P65 Activation in Triple-Negative Breast Cancer · 2025 · DOI

• However, the regulatory mechanisms governing ACSL4 expression in renal cell carcinoma (RCC) remain unclear.

  PRMT5-Mediated Arginine Methylation of ACSL4 Attenuates Its Stability and Suppresses Ferroptosis in Renal Cancer · 2025 · DOI

Most-cited papers in Cancer-related gene regulation

• Protein arginine methyltransferases: promising targets for cancer therapy · Experimental & Molecular Medicine · 2021 · 271 citations
• Cellular pathways influenced by protein arginine methylation: Implications for cancer · Molecular Cell · 2021 · 187 citations
• PRMT5 inhibition disrupts splicing and stemness in glioblastoma · Nature Communications · 2021 · 177 citations
• ENO1 Promotes Lung Cancer Metastasis via HGFR and WNT Signaling–Driven Epithelial-to-Mesenchymal Transition · Cancer Research · 2021 · 142 citations
• PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma · Nature Communications · 2023 · 127 citations
• First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: results from phase I dose exploration · Annals of Oncology · 2024 · 101 citations
• Wnt/β-catenin signalling, epithelial-mesenchymal transition and crosslink signalling in colorectal cancer cells · Biomedicine & Pharmacotherapy · 2024 · 77 citations
• AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients with MTAP-Deleted Cancers · Cancer Discovery · 2024 · 75 citations
• pRb and p16 protein alterations in human oral tumorigenesis · Oral Oncology · 1998 · 74 citations
• Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers · Journal of Medicinal Chemistry · 2024 · 68 citations

Most recent work

• MTAP Deletion in Oncogenesis: A Synthetic Lethality Scenario · Cancer Research · 2026
• Global profiling of arginine reactivity and ligandability in the human proteome · Nature Chemistry · 2026
• MTAP loss is frequent in oncogene-driven NSCLC and may confer sensitivity to combined PRMT5 inhibitors and targeted therapies · Annals of Oncology · 2026
• Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5 · Nature Chemical Biology · 2026
• Targeting ENO1 reprograms macrophage polarization to trigger antitumor immunity and improves the therapeutic effect of radiotherapy · Cell Death and Disease · 2026
• Macrophage PRMT9 Ameliorates Acute Myocardial Infarction by Promoting Symmetric Dimethylation and Degradation of STAT1 · Circulation · 2026
• Discovery of Oxime Ether Derivatives as Second-Generation PRMT5 Inhibitors for the Treatment of Triple Negative Breast Cancer · Journal of Medicinal Chemistry · 2026
• PFKM governs metabolic shifts throughout skeletal muscle differentiation · Nature Metabolism · 2026
• Reversible arginine methylation regulates mitochondrial IDH2 activity: coordinated control by CARM1 and KDM3A/4A · Cell Death and Disease · 2026
• Polyamines buffer labile iron to suppress ferroptosis · Cell · 2026

Related topics in Biochemistry, Genetics and Molecular Biology