NAR: Dongyu Zhao et al. of Peking University reveal the underlying mechanism of CHD6 transcriptional activation of carcinogenic pathways

Although CHD6 is a member of the chromatin domain helicase DNA-binding protein family, little is known about its exact role in chromatin remodeling or cancer disease
.

On November 21, 2022, Dongyu Zhao of Peking University, Kaifu Chen, Lili Zhang of Harvard University, and Cao Qi of Northwest University were present in Nucleic Acids Research (IF=19 Published online in a research paper titled "CHD6 promotes broad nucleosome eviction for transcriptional activation in prostate cancer cells," which showed CHD6 Promote extensive "excretion" of nucleosomes in prostate cancer cells to transcriptionally activate carcinogenic pathways
.
The study found that CHD6 binds to chromatin and promotes widespread "excretion" of nucleosomes, thereby activating transcriptional activation
of many cancer pathways.
By integrating multiple patient cohorts and performing bioinformatics analysis on more than a thousand prostate cancer datasets, it was found that elevated expression of CHD6 in prostate cancer was associated with
poor prognosis.

Further comprehensive experiments showed that CHD6 regulated carcinogenicity and tumor development
of prostate cancer cells in mouse transplanted tumor models.
ChIP-Seq for CHD6, along with MNase-Seq and RNA-Seq, revealed that CHD6 binds to chromatin, Clearance of nucleosomes from promoters and genomics to transcriptionally activate oncogenic pathways
.
These results demonstrate the key function
of CHD6 in activating the prostate cancer pathway.

CHD6 is a DNA-dependent ATPase
.
It has been reported to play an important role in DNA damage and repair and can be induced by treating cells with low-dose irradiation
.
When cells are subjected to chronic oxidative stress, CHD6 promotes cell survival
.
In addition, previous studies have found that liquid chromatography and tandem mass spectrometry analysis of plasma samples have shown that CHD6 is one of
many proteins in which the abundance of peptides in plasma in ovarian patients changes.
Genomic analysis revealed that CHD6 is one of
many genes that can be affected by mutations in bladder and colorectal cancer.
A case report of a 78-year-old patient with acute myeloid leukemia based on fluorescence in situ hybridization (FISH) analysis showed that genomic translocation could lead to LMBRD1-CHD6 fusion
.
Despite these observed links, the role of CHD6 in cancer compared to other CHD proteins is unclear
.

CHD6-activated gene expression is associated with poor prognosis in prostate cancer patients (Nucleic Acids Research).

Transcription factors in the E2F family program the expression
of genes that are critical for cell cycle progression.
Dysregulation of the cell cycle leads to uncontrolled proliferation of tumor cells and cancer metastasis
.
Abnormal activity of E2F1 has been observed in many cancers, including breast, non-small cell lung and prostate cancer.

E2F1 has been reported to activate EZH2 in transcription, which is required for
cancer cell proliferation.

E2F1 is negatively regulated by the tumor suppressor gene retinoblastoma 1 (RB1), whose absence in prostate cancer makes antiandrogen therapy resistant to anti-androgen therapy
.
Interestingly, of the 18 most common gene and pathway alterations in patients with metastatic castration-resistant prostate cancer, RB1 deletion was found to be most strongly associated with adverse clinical outcomes
.
Although there have been some reports of transcriptional factors on the transcriptional regulation of E2F1, the alteration of chromatin structure around the E2F1 site and how this promotes tumor progression is unclear
.

Despite the success of radiotherapy, chemotherapy, and androgen depletion therapy for many patients, prostate cancer remains the leading cause
of malignancy and cancer-related death in men worldwide.
Understanding the complete molecular mechanisms of prostate cancer is fundamental
to developing new therapeutic strategies to achieve a complete cure.
Here, the study reports on the underappreciated role of the CHD family protein CHD6 as a new oncogene for prostate cancer, elucidates how CHD6 plays an epigenetic role in the transcriptional activation of many key cancer pathways, and demonstrates CHD6 How the loss impairs the carcinogenic characteristics
of RB1-deficient prostate cancer.

Original link:

https://doi.
org/10.
1093/nar/gkac1090