PNAS: Research progress on new molecules and pathways for epitranscriptional regulation of lysosome-mediated cell death

The integrity of the lysosomal membrane is very important for the fate of the cell.
Once the permeability of the lysosomal membrane changes, a variety of hydrolases, mainly cathepsins, will be released into the cytoplasm, usually resulting in cell death, that is, lysosomes.
dependent cell death
.
Currently, multiple mechanisms exist to explain lysosomal permeability

The above findings suggest that cancer cells that are insensitive to conventional therapies may be effectively treated by using activation of the lysosomal cell death pathway
.
Furthermore, tumor cell lysosomes are more fragile than normal cells and more prone to lysosomal membrane permeability and lysosome-dependent cell death

LCDR/hnRNP K/LAPTM5 regulation pattern

Recently, researchers from the Biomarker Research Center of Suzhou Institute of Biomedical Engineering Technology, Chinese Academy of Sciences published a paper entitled LCDR regulates the integrity of lysosomal membrane by hnRNP K-stabilized LAPTM5 transcript and promotes cell survival in Proceedings of the National Academy of Sciences.
research paper
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This study reports for the first time a new epitranscriptional regulatory molecule that regulates lysosome-mediated cell death, clarifies the regulatory mechanism and clinical significance, and provides a new theoretical basis for the development of tumor biomarkers and clinical targeted therapy

The researchers systematically analyzed histone acetylation regulation and differentially expressed genes in The Cancer Genome Atlas database, and found that a new lysosome cell death regulator (LCDR) gene was significantly overexpressed in lung cancer and was under the control of the group.
Regulation of protein acetylation
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In order to study the biological function of LCDR, researchers knocked down LCDR in lung cancer cells.

In order to further elucidate the signaling pathway regulated by LCDR, the researchers confirmed by RNA pull-down, transcriptome sequencing and RNA-binding protein immunoprecipitation experiments that LCDR interacts with KH1 of heterogeneous nuclear ribonucleoprotein K (hnRNP K).
The domains combine with each other, which promotes the KH3 domain of hnRNP K protein and the 3′-terminal untranslated region of lysosomal protein transmembrane 5 (LAPTM5) to combine with each other, and improves the stability of LAPTM5 and maintains the solubility of LAPTM5.
Stabilization of lysosome membranes, thereby inhibiting lysosome-dependent cell death and promoting cell survival
.

Histone acetylation modification is an important regulatory method of epigenetics, which plays an important role in the occurrence and development of tumors by regulating gene expression in a complex and precise
manner .
Targeting histone deacetylases is a promising therapeutic strategy in cancer therapy, however, preclinical evidence suggests that single agents targeting histone deacetylases have only moderate efficacy in the treatment of cancer patients, possibly due to Drugs targeting histone deacetylases also affected secondary signaling pathways

The study also showed that the expression levels of LCDR, hnRNPK and LAPTM5 were significantly higher than those in the paracancerous tissue, and there was a significant correlation between LCDR and hnRNP K and LAPTM5 expression, and the combined LCDR/hnRNP K/LAPTM5 receiver operating curve analysis showed a higher level of expression.
High sensitivity and specificity
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In addition, we developed a nuclear-targeted nanomaterial-delivered si-LCDR and identified the feasibility of LCDR as a clinical target using a patient-derived xenograft mouse model

In conclusion, the researchers identified for the first time a novel epitranscriptional regulator that regulates lysosome-dependent cell death at the post-transcriptional level (as shown in the figure), and revealed that a novel LCDR/hnRNP K/LAPTM5 axis regulates the occurrence of lung cancer.
and development, providing a promising strategy for cancer therapy
.
The research work is supported by the National Natural Science Foundation of China and the Strategic Pilot Science and Technology Project of the Chinese Academy of Sciences