PNAS reveals: The older you get, the more likely you are to get cancer?

As the saying goes, "Years are not forgiving.
" As people get older, the risk of people suffering from diseases including cancer will increase
.

Although it has been known that this phenomenon is related to the aging of the basic unit cells that constitute the structure and function of the human body, the specific mechanism of disease caused by aging is still unknown

Recently, researchers from the Japan Society for Cancer Research and Genes published a research report titled Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer in the Proceedings of the National Academy of Sciences (PNAS), revealing To understand how aging promotes the occurrence of cancer
.

The report pointed out that a previously under-understood non-coding RNA (ncRNA) around the centromere of cell chromosomes may be the "main cause" of cancer with age, and this type of RNA can promote the senescence-related secretory phenotype (SASP) The expression of such pro-inflammatory proteins promotes the occurrence of diseases
.

This will provide new ideas for controlling "old age" diseases and helping people to better enjoy the life of old age

https://doi.
org/10.
1073/pnas.
2025647118

In order to find out the connection between cellular senescence and the occurrence of diseases, the researchers first compared the difference in gene expression between human embryonic lung fibroblasts (IMR-90) under normal proliferation and X-ray-induced senescence.
Transposition Enzyme Accessible Chromatin Sequencing (ATAC-seq) showed that the peak intensity of a total of 16,325 points changed significantly
.

By integrating these data with published data, the researchers "smelt" something unusual.
A kind of ncRNA called "Human Satellite II" (hSATII) in the centromeric part of cell chromosomes is expressed in normal cells.
It is genetically silent, but remains open in senescent cells
.

If hSATII RNA is overexpressed in cells, it will induce SASP-like inflammatory gene expression

Pericentric hSATII RNA regulates SASP factor gene expression during cell aging

Cell senescence will cause significant changes in its chromatin organization, this process is participated by CCCTC-binding factor (CTCF)
.

CTCF is a multifunctional transcription factor widely found in eukaryotes.

In order to solve the mystery, the researchers identified 26 chromatin-binding proteins of hSATII RNA through gene ontology (GO) analysis, and focused on CTCF, the RNA-binding protein
.

RNA immunoprecipitation analysis showed that when CTCF is missing, the expression of SASP-like inflammatory genes caused by hSATII RNA will be significantly up-regulated, and when this regulatory factor is overexpressed, the expression of SASP-like inflammatory genes will be down-regulated

CTCF regulates the expression level of hSATII RNA

Previous studies have shown that human satellite RNA may induce chromosomal instability (CIN), which is a risk factor for the occurrence and development of cancer
.

Therefore, in further analysis, the researchers explored whether the interference of hSATII RNA on CTCF function can induce CIN, and found that cells with hSATII RNA overexpression showed obvious CIN characteristics and tumor cell phenotypes, while CTCF overexpression eliminated hSATII RNA-induced CIN indicates that hSATII may promote the occurrence of cancer as cells age

In addition, the researchers also found that hSATII RNA in senescent cells can be transferred to surrounding normal cells through extracellular vesicles (EV), thereby promoting the expression of SASP-like inflammatory genes in other cells and the occurrence of CIN
.

In summary, this report highlights the role of hSATII RNA near the centromere in the occurrence and development of cancer with aging.
It can promote tumor development by regulating SASP-like inflammatory factors and EVs metastasis
.

This will bring new prevention and treatment strategies to fight against age-related diseases in the future

Reference materials:

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