Abstract

Background

   Belonging to the protein arginine methyltransferase (PRMT) family, the
   enzyme encoded by coactivator associated arginine methyltransferase 1
   (CARM1) catalyzes the methylation of protein arginine residues,
   especially acts on histones and other chromatin related proteins, which
   is essential in regulating gene expression. Beyond its well-established
   involvement in the regulation of transcription, recent studies have
   revealed a novel role of CARM1 in tumorigenesis and development, but
   there is still a lack of systematic understanding of CARM1 in human
   cancers. An integrated analysis of CARM1 in pan-cancer may contribute
   to further explore its prognostic value and potential immunological
   function in tumor therapy.

Results

   Based on systematic analysis of data in multiple databases, we firstly
   verified that CARM1 is highly expressed in most tumors compared with
   corresponding normal tissues, and is bound up with poor prognosis in
   some tumors. Subsequently, relevance between CARM1 expression level and
   tumor immune microenvironment is analyzed from the perspectives of
   tumor mutation burden, microsatellite instability, mismatch repair
   genes, methyltransferases genes, immune checkpoint genes and immune
   cells infiltration, indicating a potential relationship between CARM1
   expression and tumor microenvironment. A gene enrichment analysis
   followed shortly, which implied that the role of CARM1 in tumor
   pathogenesis may be related to transcriptional imbalance and viral
   carcinogenesis.

Conclusions

   Our first comprehensive bioinformatics analysis provides a broad
   molecular perspective on the role of CARM1 in various tumors,
   highlights its value in clinical prognosis and potential association
   with tumor immune microenvironment, which may furnish an immune based
   antitumor strategy to provide a reference for more accurate and
   personalized immunotherapy in the future.

Supplementary Information

   The online version contains supplementary material available at
   10.1186/s12863-021-01022-w.

   Keywords: CARM1, Pan-cancer analysis, Prognosis, Immune, Tumor
   microenvironment

Background

   Due to the heterogeneity and diversity of tumors, the deficiency of
   effective biomarkers represents one of the main bottlenecks restricting
   the development of cancer medicine. The accumulated big data analysis
   of any gene of interest has become a powerful means to explore the
   complex process of tumorigenesis and development. Analyzing gene
   expression and related genetic modification allows us to evaluate its
   clinical prognosis and explore related signaling pathways, which could
   help to find new immunotherapy targets.

   CARM1, also known as PRMT4, located in Chr19p13.2 (Fig. [37]1a), was
   first identified as an arginine methyltransferase that introduces
   asymmetric methylation of arginine residues in histone H3 and other
   chromatin-associated proteins [[38]1]. With regard to human CARM1
   protein, it is composed of an N-terminal pleckstrin homology-like
   domain (PH-like), a C-terminal transactivase domain, and a central
   catalytic domain containing the four conserved PRMT motifs
   (Fig. [39]1b). The N- and C-terminal domains of CARM1 are vital for
   substrate recognition and transcription-mediated activation [[40]2],
   and the motifs in central catalytic domain are essential for binding of
   the cofactor S-adenosyl methionine (SAM) and the substrate arginine
   [[41]3]. Long known as a transcriptional coactivator, recent studies
   have shown that it is also involved in the regulation of metabolism
   [[42]4–[43]6], autophagy [[44]7], RNA regulation [[45]8] and early
   mammalian development [[46]9]. Recently, accumulating evidence has
   suggested that CARM1 also has an impact on the occurrence and
   development of tumors [[47]10–[48]14]. Existing studies on exploring
   the mechanisms of CARM1 methylation affecting tumor progression have
   shown that CARM1 is a coactivator of several cancer-related
   transcription factors and can be involved in promoting tumor cell
   proliferation and metastasis by methylating cancer-related
   transcription factors, including NF-κB, p53, steroid receptors and so
   on, and its high expression is associated with poor prognosis of tumors
   [[49]15]. For example, in the most studied breast cancer, CARM1 could
   methylate the R838 site of lysine demethylase 1 (LSD1) to promote the
   binding of deubiquitinase USP7, resulting in the ubiquitination and
   stabilization of LSD1, thereby promoting the invasion and metastasis of
   breast cancer cells [[50]16]. In addition, CARM1 has been found to be
   involved in regulating metabolic pathways in tumors. Metabolic
   reprogramming is a hallmark of cancer. In breast cancer cells,
   methylation of the key glycolytic enzyme pyruvate kinase M2 isoform
   (PKM2) by CARM1 shifts the metabolic balance from oxidative
   phosphorylation to aerobic glycolysis, producing a large amount of ATP,
   so as to promote tumor cell proliferation and migration [[51]4].
   Nevertheless, CARM1 is up-regulated when glucose starvation, followed
   by methylation of GAPDH to inhibiting glycolysis, thereby suppressing
   tumor cell proliferation in liver cancer cells [[52]6], which is to
   some extent consistent with the results of the correlation analysis
   between CARM1 expression and liver cancer prognosis described in our
   work. Current evidence about effects of CARM1 on various cancers has
   been shown in Fig. [53]1c and Table [54]4 [[55]5, [56]6, [57]13,
   [58]16–[59]25].

Fig. 1.

   [60]Fig. 1
   [61]Open in a new tab

   Basic information about CARM1. a Genomic location of human CARM1. b
   Protein structure diagram of human CARM1. c According to the reported
   studies, the carcinogenic pathways CARM1 was involved in across
   different cancers are shown graphically. The related references are