KEY TAKEAWAYS
- The study aimed to examine the impact of DCBLD1 overexpression on activating the PPP and its role in driving cervical cancer progression in cervical cancer pts.
- Researchers concluded that lactylation-induced post-translational modification of DCBLD1, promotes cervical cancer progression through the activation of PPP.
Discoidin, CUB, and LCCL domain-containing type I (DCBLD1) have been recognized as oncogenes implicated in the multifaceted regulation of tumor progression, particularly in cervical cancer. Despite this identification, the specific mechanisms underlying DCBLD1’s involvement in cervical cancer remain unclear. Notably, lactate-mediated lactylation has been identified as a modulator of protein function, but whether DCBLD1 undergoes modification through lactylation and the functional implications of such lactylation are currently unknown.
Qingfei Meng and her team aimed to elucidate the intricate mechanism by which lactylation modification contributes to the stabilization of the DCBLD1 protein.
They performed an inclusive analysis of DCBLD1 expression in human cervical cancer cells and adjacent non-tumorous tissues. Quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry techniques were utilized for precise examination. In vitro and in vivo studies were conducted to discern the impact of DCBLD1 on cervical cancer progression.
For a comprehensive understanding of DCBLD1-induced metabolite alterations, untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics studies were employed. The degradation of G6PD by DCBLD1, activated through autophagy, was detected using western blot, immunofluorescence, and transmission electron microscopy.
To elucidate the mechanism behind lactate-induced DCBLD1 transcription, they employed chromatin immunoprecipitation and a dual luciferase reporter assay. Additionally, specific modification sites within the DCBLD1 protein were verified using LC-MS/MS.
The study showed that lactate significantly increased DCBLD1 expression, activating the pentose phosphate pathway (PPP) and subsequently promoting proliferation and metastasis in cervical cancer cells. DCBLD1 played a pivotal role in stimulating PPP by upregulating glucose-6-phosphate dehydrogenase (G6PD) expression and enzyme activity. This mechanism was associated with the heightened enrichment of HIF-1α in the DCBLD1 promoter region, ultimately enhancing DCBLD1 mRNA expression.
Furthermore, the study revealed that lactate-induced DCBLD1 lactylation contributed to the stabilization of DCBLD1 expression. DCBLD1 was identified as a substrate for lactylation, with a predominant lactylation site identified at K172. This post-translational modification played a crucial role in preventing DCBLD1 degradation.
DCBLD1 overexpression was found to inhibit the autophagic degradation of G6PD, consequently activating the PPP and promoting the progression of cervical cancer. In vivo experiments demonstrated that 6-An, a mediator, inhibited G6PD enzyme activity, inhibiting tumor proliferation.
The study concluded that a novel post-translational modification of DCBLD1, driven by lactylation, holds significant importance. This modification plays a pivotal role in mediating the PPP, ultimately promoting the progression of cervical cancer.
The study is sponsored by National Natural Science Foundation of China, National Key Research and Development Program of China, Science and Technology Department of Jilin Province
Source: https://pubmed.ncbi.nlm.nih.gov/38291438/
Meng Q, Sun H, Zhang Y, et al.” Lactylation stabilizes DCBLD1 activating the pentose phosphate pathway to promote cervical cancer progression. J Exp Clin Cancer Res. 2024 Jan 31;43(1):36. doi: 10.1186/s13046-024-02943-x. PMID: 38291438; PMCID: PMC10829273.
