Decoding the ribosome's hidden language: rRNA modifications as key players in cancer dynamics and targeted therapies

Abstract

Ribosomal RNA (rRNA) modifications, essential components of ribosome structure and function, significantly impact cellular proteomics and cancer biology. These chemical modifications transcend structural roles, critically shaping ribosome functionality and influencing cellular protein profiles. In this review, the mechanisms by which rRNA modifications regulate both rRNA functions and broader cellular physiological processes are critically discussed. Importantly, by altering the translational output, rRNA modifications can shift the cellular equilibrium towards oncogenesis, thus playing a key role in cancer development and progression. Moreover, a special focus is placed on the functions of mitochondrial rRNA modifications and their aberrant expression in cancer, an area with profound implications yet largely uncharted. Dysregulation in these modifications can lead to metabolic dysfunction and apoptosis resistance, hallmark traits of cancer cells. Furthermore, the current challenges and future perspectives in targeting rRNA modifications are highlighted as a therapeutic approach for cancer treatment. In conclusion, rRNA modifications represent a frontier in cancer research, offering novel insights and therapeutic possibilities. Understanding and harnessing these modifications can pave the way for breakthroughs in cancer treatment, potentially transforming the approach to combating this complex disease.

Keywords: cancer biology; rRNA modification; therapeutic potential.

FIGURE 1

Type of rRNA modifications and their impact on ribosome function. rRNA undergoes various modifications, notably 2′‐OMe, m⁶A, m⁵C, Ψ, and m¹A, which are pivotal in regulating ribosome functionality and cellular processes. These modifications are essential in maintaining rRNA stability, facilitating rRNA processing, and enhancing the fidelity and efficiency of protein synthesis. Furthermore, they also contribute significantly to ribosome biogenesis, and playing a crucial role in maintaining the structural integrity and functionality of ribosomes. Created with BioRender.com.

FIGURE 2

Regulatory role of rRNA modifications in biological and cellular functions. Various modifications of rRNA are known to play critical roles in the regulation of cellular functions. Through next‐generation sequencing, it has been elucidated that numerous RNA modification enzymes, such as TRMT112, METTL5, NSUN1/5, ZCCHC4 etc., along with snoRNAs, play pivotal roles in mediating rRNA modification. This dynamic modification process intricately regulates the synthesis of related proteins, thereby influencing diverse cellular functions including cell proliferation, differentiation, immune response, and oxidative stress response. Consequently, these modifications exert profound effects on an individual's developmental processes, behavioural patterns, and overall survival and growth status. Created with BioRender.com.

FIGURE 3

Regulation of mitochondrial rRNA modification. Mitochondrial rRNA undergoes various modifications, including 2′‐OMe, m⁴C, m⁶A, m⁵C, m⁵U, m¹A, among others. Proper modifications of mitochondrial rRNA are crucial for the biogenesis of mitochondrial ribosomes, enhancing protein synthesis efficiency and facilitating the formation and function of key components in the mitochondrial respiratory chain. Alterations in the expression levels of enzymes such as METTL15, METTL17, and MRM2 lead to changes in mt‐rRNA modification, impacting ribosome assembly and protein translation. This, in turn, can impair essential mitochondrial functions, notably OXPHOS. TRMT2B, which catalyses the m⁵U modification of human 12S mitochondrial rRNA, plays a regulatory role rather than being essential for mitochondrial rRNA stability and mitochondrial translation. Created with BioRender.com.

FIGURE 4

Clinical relevance of rRNA modifications in cancer. rRNA modifications play a pivotal role in regulating protein synthesis and cellular functionality, making significant contributions to the development and progression of tumours. A. Increasingly, these modifications are recognised as hallmarks of cancer, influencing drug resistance, tumour development, and metastasis. Aberrant rRNA modifications, such as single nucleotide variants in 18S rRNA impacting the ancient m¹acp³Ψ modification in colorectal cancer, is a notable example. B. Advanced techniques like and RiboMeth‐seq has revealed variability in Ψ and 2′‐O‐methylation levels in cancer. C. Specific rRNA modifications in HGG (high‐grade glioma) emerge as promising therapeutic targets. There is exploration into the potential of using drugs to modulate enzyme activities responsible for rRNA modifications, utilising rRNA modification patterns as predictive biomarkers for treatment efficacy. Notably, in glioma, the profound impact of mitochondrial rRNA modifications on mitochondrial functionality significantly influences energy production, metabolism, and the tumour microenvironment. Created with BioRender.com.

FIGURE 5

Role of METTL5/TRMT112 complex and NSUN5 in rRNA modification and cancer progression. A. METTL5‐mediated m6A modification of 18S rRNA at adenosine 1832 plays a vital role in mRNA binding, ribosome functionality, and the proliferation of cancer cells, notably in breast and pancreatic cancers. B. Furthermore, increased activity of the METTL5‐TRMT112 complex is linked to adverse cancer prognosis, mediated by compromised ribosome function and altered fatty acid metabolism. This connection suggests a promising therapeutic target for hepatocellular carcinoma. C. In intrahepatic cholangiocarcinoma, aberrant METTL5‐mediated m6A modification of 18S rRNA disrupts TGF‐β pathway translation, leading to poorer survival outcomes and accelerated cancer progression. D. Additionally, NSUN5 modifies cytosine 3782 in 28S rRNA, which enhances protein synthesis. Its overexpression is associated with accelerated growth and treatment resistance in glioma, whereas its inactivation appears to suppress tumour development and increase cellular sensitivity to therapeutic interventions. Created with BioRender.com.

FIGURE 6

snoRNA‐mediated rRNA modification and its implications in cancer. Various snoRNAs exhibit distinct functions across different types of cancer. In rRNA modification, snoRNA promotes cancer cell proliferation and invasion while inhibiting autophagy through the enhancement of oncogene translation, among other pathways. Additionally, ncRNA indirectly regulates snoRNA by controlling the expression of NOP58. The snoRNA‐mediated rRNA 2΄‐OMe modification plays a facilitating role in cancer by promoting cell proliferation, invasion, and metastasis, potentially impacting tumour prognosis and treatment response. In addition, snoRNA‐mediated rRNA Ψ modification fosters cancer development by influencing mitochondrial function, triggering ferroptosis, and other pathways that contribute to cancer cell viability. Created with BioRender.com.

FIGURE 7

Additional key regulators of rRNA modifications in cancer. A. Overexpression of FBL in p53‐deficient cancer cells leads to altered rRNA methylation patterns, significantly impacting breast cancer progression. B. The loss of ZCCHC4 and the associated m⁶A₄₂₂₀ modification in 28S rRNA results in reduced global translation and impairs HCC growth. C. In Dkc1 mutant mice, early disruptions in rRNA psudouridylation precede DC symptoms, suggesting ribosome dysfunction as an initiator of DC. Telomere shortening in later generations contributes to DC progression and potential cancer susceptibility. D. Moreover, the SREBF2‐FOXM1 axis and ACA43 are critical in modulating 28S rRNA Ψ in small nucleolar RNA, affecting the progression of glioma‐initiating cells. This highlights the vital role of genetic factors and rRNA modifications in various cancers. E. U50 down‐regulation in cancers like colon cancer leads to diminished C2848 methylation of 28S rRNA, compromising ribosome function and cell proliferation. Created with BioRender.com.