Differentiated from antecedent studies, which focused solely on the subunits of the PRC2 complex, our study analyzed the PRC2 complex as an entirety in transcriptome for the first time. Our observations confirmed evidence for previous studies in biological function and provided a more systematic, novel, possible perspective to dissect the role of PRC2 complex in tumor promotion by bioinformatics. While extensive research efforts remain to be invested in decoding PRC2’s precise mechanistic roles in tumor immunity, the gleaned insights thus far open up promising therapeutic avenues. These revelations, in potentiality, could catalyze the evolution of innovative immunotherapy strategies, enhancing patient prognoses and furthering the frontiers of tumor immunity research.
At its core, the PRC2 complex is comprised of three quintessential components: EZH2, SUZ12, and EED. Within the mammalian immune paradigm, a preponderance of research has revolved around EZH2, which exhibits pronounced expression in proliferative cell types. Both EZH2 and its fellow PRC2 constituents are essential for hematopoietic stem cell functionality and the maturation of lymphocytes. Several scholarly inquiries propose that the holistic PRC2 complex is intrinsically linked with cellular proliferation, invasion, and metastasis. Our postulations suggest that the co-expression of EZH2, SUZ12, and EED, which collectively form the PRC2 complex, correlates with the unfavorable prognosis observed in BRCA patients. Consequently, we embarked on unraveling the significance of the PRC2 complex in tumor progression dynamics. EZH2 functions as an enzyme orchestrating pivotal roles in genomic transcriptional regulation, primarily effectuating gene repression through histone tail deacetylation. Both the mRNA and protein expressions of EZH2 are ubiquitously upregulated across myriad cancers, positioning it as a potential catalyst for tumorigenesis and progression. Contemporary studies have illuminated the association between EZH2 and tumor immunity—a mechanism wherein the innate immune system combats malignancies, predominately by amplifying the cytotoxic effects of immune cells against tumor entities. However, tumors often elude this immune surveillance by modulating various immunosuppressive agents within the TME. Intriguingly, EZH2 has been implicated in the regulation of a plethora of these immunosuppressive factors in the TME, effectively dampening immune cell activity. For instance, studies have documented EZH2’s ability to impede the functionality of immunosuppressive entities, such as regulatory T cells and tumor-associated macrophages, attenuating their tumor-suppressing effects. Additionally, EZH2 can hinder the expression of tumor antigens, undermining the detection and eradication of tumor cells by the immune system. Consequently, an elevated expression of EZH2 might foster tumor immune evasion, expediting tumor growth and metastasis. The advent of EZH2 inhibitors is considered a promising therapeutic avenue. Preliminary findings suggested that EZH2 inhibition can rejuvenate tumor antigenic expression and fortify the cytotoxic prowess of immune cells against tumors, while concurrently enhancing the overall functionality of these immune cells.
EZH2 is instrumental in the differentiation and maturation of various immune cells, encompassing B cells, T cells, innate lymphocytes, and myeloid cells [18]. It is pivotal to underline that EZH2 is central to steering the trajectory and plasticity of helper T cell differentiation [32]. Existing literature posits that EZH2 actively orchestrates both Th1 and Th2 differentiation. There’s empirical evidence suggesting that EZH2 augments the genesis of Th1 cells via a combined mechanism of transcriptional and post-transcriptional regulation of T-bet [33]. Furthermore, EZH2, being abundantly present in CD4 + T cells, associates with the Gata3 locus preceding Th2 cell differentiation [34]. Contrarily, studies delineate that while EZH2 propels Th1 differentiation, it acts inversely on Th2 differentiation, especially in the context of allergic rhinitis [35]. Damon et al. proposed a nuanced understanding, articulating that EZH2 intrinsically restricts the differentiation and plasticity of Th1 and Th2 cells [36]. Additionally, the ablation of EZH2 not only stymies CD4 + CD25 + FOXP3 + regulatory T cells but also catalyzes the production of CD8 + cytotoxic T lymphocytes potent at eradicating tumor cells, especially evident in non-small cell lung cancer contexts [37].
Given EZH2’s paramount role in tissue morphogenesis and cellular destiny determination[38], coupled with its influence over differentiation trajectories of cells emanating from hematopoietic stem cells, it’s plausible that the immune cell maturation could be a target for EZH2-mediated actions. Intriguingly, PRC2, the only known methyltransferase exhibiting activity toward H3K27, accounts for all H3K27 methylation in mouse embryonic stem cells[39]. PRC2, an epigenetic modification ensemble, wields significant regulatory clout within cellular dynamics. Tumor immunity epitomized the body’s defensive stratagem against neoplastic cells via the immune apparatus. A burgeoning body of contemporary research accentuates PRC2’s salient role in tumor immunity. Mechanistically, PRC2 modulates gene expression by appending methyl moieties onto chromatin-associated histones. Myriad studies have elucidated that PRC2’s immersion in tumor immunity predominantly pivots around modulating cardinal immune genes. For instance, PRC2 can suppress the transcription of immune antigens, thereby attenuating the immune system’s recognition and subsequent assault on tumor cells. Moreover, PRC2 can stifle the transcription of immune checkpoint molecules within tumor cells, thereby further enervating the immune system’s efficacy.
Disconcertingly, anomalous expression patterns of PRC2 have been strongly correlated with oncogenesis and its subsequent progression. Exaggerated PRC2 expression has been linked with the exacerbation and adverse prognosis of several malignancies. Augmented EZH2, EED, and SUZ12 mRNA expression were largely correlated with shorter disease-free survival [40]. Multiple studies have confirmed overexpression of EZH2 has a worse survival of patients with TNBC [41, 42]. Researchers also have found that the expression of SUZ12 was significantly increased in gastric tumors and associated with shorter overall survival of patients [43]. Akin to SUZ12, higher expression of EED in gastric tumor tissues, indicating dismal prognoses [44]. Thus, modulating the PRC2’s activity or interfering with its molecular interactions could herald a revolutionary paradigm in tumor immunotherapy. Th2 and innate lymphoid cells 2 can fortify tumor growth by secreting pro-tumorigenic cytokines such as IL-4, IL-5, and IL-13. Alam et.al found that fungal mycobiome promotes type-2 immune responses by IL-33 secretion in pancreatic cancer [45]. In this study, we observed that the PRC2 complex remodeled the tumor immunosuppressive microenvironment in breast cancer by regulating higher infiltration of Th2 cells, which may be a bridge between poor prognosis with PRC2 complex. Antecedent research has alluded to an unorthodox function of EZH2 in augmenting cytokine gene expression in Th cells. Consequently, dissecting the intricate relationship between the PRC2 complex and immune cell development becomes a tantalizing research avenue. Furthermore, PRC2, being a pivotal epigenetic mediator of immune evasion in leukemia[46], has been spotlighted by Marian et al. They postulated that PRC2 orchestrates a coordinated transcriptional silencing of the MHC-I antigen processing trajectory, thereby foresting immune evasion in neoplasms[47]. Remarkably, molecules targeting PRC2 have been taxonomized into three primary classes: (i) those that inhibit EZH2’s enzymatic prowess, (ii) compounds that bind to EED, impeding its interaction with H3K27, and (iii) agents that tether either to EZH2 or EED, including their proteasomal degradation, inclusive of an array of inhibitors and degraders[48]. Such molecule interventions against PRC2 are anticipated to profoundly influence BRCA treatment modalities.
This study also has a few limitations that warrant attention and further investigation. We only conducted bioinformatics analyses involving the potential function of the PRC2 complex, including the relationship with cell proliferation and immune cells in TME but lack biological functional experimental evidence to support it. Although our study showcased the capability of the PRC2 complex to inhibit modification and proliferation in tumor cells in RNA expression, its in vitro and vivo efficacy remains unclear. Addressing these limitations through subsequent research endeavors could significantly enhance the translational relevance of our findings. Comprehensive and in-depth experiments or the underlying mechanism investigations need to be done in our future study.