Enzyme Rivalry in Tumors: How Arginine Methyltransferases Cooperate and Compete in Cancer

Protein arginine methyltransferases, a family of nine enzymes known as PRMTs, have long been studied as individual drivers of cancer. A new review published in Epigenetics & Chromatin argues that this one-enzyme-at-a-time view misses the most important part of the story: the way these enzymes talk to each other. Yu Han, Lie Ma, Xiangyu Ma and Baiqu Huang synthesize evidence that different PRMTs can reinforce one another’s tumor-promoting work in some contexts and directly sabotage each other in others, a duality with major consequences for how PRMT-targeted drugs should be designed and deployed.

PRMTs catalyze the transfer of methyl groups from S-adenosylmethionine onto the guanidino nitrogen atoms of arginine residues in histone and non-histone proteins. Based on the reaction products, the family divides into three functional subtypes. Type I enzymes, including PRMT1, PRMT2, PRMT3, PRMT4/CARM1, PRMT6 and PRMT8, attach two methyl groups to a single nitrogen atom, generating asymmetric dimethylarginine. Type II enzymes, PRMT5 and PRMT9, place one methyl group on each of the two nitrogen atoms, producing symmetric dimethylarginine. PRMT7, the sole type III member, adds only a single methyl group. These chemically distinct marks are read differently by the cell, which is precisely why the identity of the writing enzyme matters as much as the site being modified.

The clearest example of enzymatic rivalry centers on histone H4 arginine 3. PRMT1, which accounts for roughly 85 percent of arginine methylation in mammalian cells, deposits an asymmetric dimethylation mark at H4R3 that is recognized by the Tudor-domain reader TDRD3 and helps assemble transcriptional activation complexes. PRMT5 writes the symmetric dimethylation mark on the very same residue; that version recruits the ADD domain of DNMT3A, drawing DNA methyltransferases to chromatin and silencing tumor suppressor genes. The review frames this pair of opposing marks as a core epigenetic switch between gene activation and repression, one in which the same amino acid carries two contradictory messages depending on which enzyme got there first.

Competition over non-histone substrates tells a similar story. In human osteosarcoma cell lines, PRMT1 and PRMT5 methylate the transcription factor E2F-1 at the same site, with each enzyme’s modification impeding the other’s. PRMT1 methylation favors E2F-1-dependent cell death, whereas PRMT5 methylation locks E2F-1 into a cell-cycle progression mode that supports proliferation. In lung cancer cells, the two enzymes competitively modify CFLARL, a regulator of the extrinsic apoptosis pathway: knocking down PRMT5 or overexpressing PRMT1 promoted apoptosis induced by doxorubicin and pemetrexed, while the reverse manipulations protected cells from chemotherapy-induced death. In glioblastoma stem cells, PRMT5-mediated symmetric dimethylation of the Myc protein protects it from degradation, while PRMT1-mediated asymmetric dimethylation promotes Myc turnover.

Yet the same enzyme pair can also cooperate. In a small cell lung cancer relapse model treated with cisplatin and etoposide, PRMT5 expression rose after chemotherapy and its methylation of CRIP1 at residues R26 and R68 activated Wnt/beta-catenin signaling, driving a stemness phenotype in surviving cells. Later in relapse, PRMT1 expression increased and its methylation of CRIP1 at R16 promoted rapid proliferation of stem-like cells. The review interprets this sequence not as simple competition but as a time-dependent functional relay, in which the two enzymes alternate control of the same substrate across stages of disease progression. The authors propose that such temporal switching may underlie what looks like antagonism in static experiments.

Synergy extends well beyond shared substrates. PRMT1 and PRMT5 both methylate the Hedgehog pathway effector GLI1, with PRMT5 stabilizing the protein through methylation at multiple arginine residues and PRMT1 boosting its transcriptional activity through methylation at position 597, together supporting the survival of pancreatic ductal adenocarcinoma cells. In breast, colorectal and prostate cancer, PRMT4, PRMT5 and PRMT7 jointly methylate multiple arginine sites on the splicing factor hnRNPA1, promoting cancer cell growth. Metabolic reprogramming offers another arena of coordination: PRMT6 enhances the activities of 6PGD and ENO1 in lung cancer, PRMT1 promotes aerobic glycolysis in non-small cell lung cancer by shifting the PKM2/PKM1 ratio, and PRMT3 drives glycolysis in liver cancer and glioblastoma through interactions with PDHK1 and HIF1A.

DNA damage repair reveals perhaps the most consequential cooperation. PRMT1 methylates the GAR motif of MRE11, which is required for its exonuclease activity and recruitment to DNA breaks, and methylates BRCA1 to promote homologous recombination in breast cancer cells. PRMT5 methylates KLF4, stabilizing it to support DNA resection and BRCA1 recruitment, also within the homologous recombination pathway. The two enzymes additionally cooperate on 53BP1, a factor that channels repair toward non-homologous end joining: in cervical cancer and neuroblastoma cells, PRMT1 methylation promotes 53BP1 binding to DNA while PRMT5 methylation enhances the protein’s stability. Because radiation and many chemotherapies work by inflicting DNA damage, this coordinated repair machinery directly undermines treatment.

These interaction networks carry a clear therapeutic implication: blocking a single PRMT may simply leave its partners to compensate. In cell line studies of small cell lung cancer and pancreatic cancer, combined inhibition of PRMT1 and PRMT5 produced synergistic suppression of tumor cell proliferation. Combining the type I inhibitor GSK3368715 with the PRMT5 inhibitor GSK3203591 strongly synergized against pancreatic cancer and diffuse large B-cell lymphoma cell lines over specific concentration ranges. Combined inhibition of PRMT4, PRMT5 and PRMT7 outperformed any single-agent approach in breast, colorectal and prostate cancer models. Genetic evidence of redundancy between PRMT4 and PRMT6, both of which can deposit the H3R17me2a activation mark, reinforces the case for multi-target strategies.

Clinical translation, however, remains uneven. Among type I inhibitors, GSK3368715 reached phase I trials for refractory diffuse large B-cell lymphoma and certain MTAP-deficient solid tumors, but the trial was terminated for lack of clinical efficacy. PRMT5 inhibitors have fared better: GSK3326595 advanced into phase I/II trials for solid tumors, non-Hodgkin lymphoma, myelodysplastic syndromes and acute myeloid leukemia, while JNJ-64619178 and the agents PRT543 and PRT811 also entered clinical testing. Most other PRMT-targeting inhibitors, including dual PRMT4/PRMT6 inhibitor MS049 and the type I inhibitors MS023 and AMI-1, remain preclinical, and for some family members no specific inhibitors exist at all.

The review’s authors are candid about the limits of the evidence. Findings on PRMT interplay derive largely from in vitro cell-based assays and animal models, often relying on limited cell lines or single models without systematic cross-tumor-type comparisons. PRMTs can even show opposing functions within the same cancer type; PRMT1, for instance, promotes epithelial-mesenchymal transition in gastric cancer cells while simultaneously inhibiting their proliferation. The authors call for inducible degradation systems and time-resolved chromatin profiling to map the sequential activity of PRMTs during tumor progression, and for longitudinal biopsy sampling in inhibitor trials to identify the clinical windows in which PRMT activity switches. Their central conclusion is that stage-specific and multi-target inhibition, matched to the shifting crosstalk among these enzymes, may ultimately deliver more effective tumor control than any single-agent strategy now in the clinic.

Subject of Research: Crosstalk among protein arginine methyltransferases in cancer biology and therapy

Article Title: Protein arginine methyltransferase crosstalk: decoding the synergistic-antagonistic axis in cancer therapy

Article References: Han, Y., Ma, L., Ma, X., & Huang, B. (2026). Protein arginine methyltransferase crosstalk: decoding the synergistic-antagonistic axis in cancer therapy. Epigenetics & Chromatin, 19(1), Article 45. https://doi.org/10.1186/s13072-026-00693-y

Image Credits: AI Generated

DOI: 10.1186/s13072-026-00693-y

Keywords: PRMTs, arginine methylation, epigenetics, cancer therapy, PRMT1, PRMT5, PRMT inhibitors, histone code, drug resistance, combination therapy, tumor metabolism, DNA damage repair