DPY30 knockdown suppresses colorectal carcinoma progression via inducing Raf1/MST2-mediated apoptosis
HaiFeng Jiang1,2, WeiChao Su1,3, HaiXing Wang4
1Department of Colorectal Tumor Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, Fujian Province, China.
Abstract:
Colorectal Carcinoma (CRC) is one of the most common malignant tumors of the digestive tract, with a high mortality rate. DPY30 is one of the core subunits of the histone methyltransferase complex, which was involved in many cancer processes. However, the role of DPY30 in the occurrence and progression of CRC remains unclear. In this study, we sought to evaluate the role and mechanism of DPY30 in CRC cells apoptosis. Here, we identified that knockdown of DPY30 significantly inhibited the HT29 and HCT116 cells proliferation in vitro. Moreover, the knockdown of DPY30 significantly increased the apoptosis rate and promoted the expression of apoptosis-related proteins in CRC cells. Meanwhile, DPY30 knockdown promoted CRC cells apoptosis through endogenous programmed death and in a caspase activation-dependent manner. Furthermore, RNA-seq analysis revealed that the action of DPY30 is closely related to the apoptosis biological processes, and screened its potential effectors Raf1. Mechanistically, DPY30 downregulation promotes MST2-induced apoptosis by inhibiting Raf1 transcriptional activity through histone H3 lysine 4 trimethylation (H3K4me3). In vivo experiments showed that DPY30 was correlated with Raf1 in nude mouse subcutaneous xenografts tissues significantly. Clinical colorectal specimens further confirmed that overexpression of DPY30 in malignant tissues was significantly correlated with Raf1 level. The vital role of the DPY30/Raf1/MST2 signaling axis in the cell death and survival rate of CRC cells was disclosed, which provides potential new targets for early diagnosis and clinical treatment of CRC.
Insights
Downregulating DPY30 inhibits colorectal cancer cell growth and promotes apoptosis by affecting the Raf1/MST2 pathway. This discovery offers new therapeutic targets for colorectal carcinoma (CRC).
Area of Science:
- Molecular Biology
- Oncology
- Epigenetics
Background:
- Colorectal carcinoma (CRC) presents a significant global health challenge due to its high mortality rate.
- The precise role of DPY30, a core subunit of the histone methyltransferase complex, in CRC pathogenesis remains largely undefined.
- Understanding DPY30's function is crucial for developing novel therapeutic strategies against CRC.
Purpose of the Study:
- To investigate the role and underlying mechanisms of DPY30 in colorectal cancer cell apoptosis.
- To elucidate the DPY30/Raf1/MST2 signaling axis in CRC progression and cell survival.
Main Methods:
- In vitro studies involving knockdown of DPY30 in HT29 and HCT116 CRC cell lines.
- Assessment of cell proliferation, apoptosis rates, and expression of apoptosis-related proteins.
- RNA-sequencing (RNA-seq) analysis to identify DPY30's interacting pathways and effectors, including Raf1.
- In vivo experiments using nude mouse subcutaneous xenografts and analysis of clinical colorectal specimens.
Main Results:
- DPY30 knockdown significantly inhibited CRC cell proliferation and increased apoptosis rates.
- DPY30 downregulation promoted CRC cell apoptosis via endogenous programmed death in a caspase-dependent manner.
- RNA-seq identified a link between DPY30 and apoptosis, pinpointing Raf1 as a potential effector.
- DPY30 inhibition promoted MST2-induced apoptosis by suppressing Raf1 transcriptional activity through H3K4me3 modification.
- DPY30 and Raf1 expression levels were significantly correlated in both in vivo xenograft models and clinical CRC tissues.
Conclusions:
- DPY30 plays a critical role in regulating colorectal cancer cell apoptosis and proliferation.
- The DPY30/Raf1/MST2 signaling axis is vital for controlling CRC cell death and survival.
- Targeting the DPY30/Raf1/MST2 pathway presents a promising avenue for early diagnosis and clinical treatment of colorectal carcinoma.
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