Recently, the team of Yuan Kai, the researcher of Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, and Director of the Biobank of Xiangya Hospital, Central South University, published a research article titled “ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription” in Nature Communications, revealing that tumor suppressor ARIDIA loss activated a group of human endogenous retrovirus-H (HERVH) to modulate BRD4-dependent transcription. This study suggests that HERVH is promising to become a new target to treat colorectal cancer. Prof. Yuan Kai is independent corresponding author of this paper. Yu Chunhong, the postdoctoral fellow of Xiangya Hospital, and doctoral student Lei Xiaoyun in 2018 of Central South University, are the co-first authors. The Department of Medical Oncology of Xiangya Hospital is the first affiliation. This work is supported by Prof. Chen Xiang and Prof. Yin Mingzhu from the Department of Dermatology and Prof. Fu Kai from Hunan Key Laboratory of Molecular Precision Medicine.
The team of Yuan Kai found that many Transposable elements (TEs), especially the pluripotency-related human endogenous retrovirus H (HERVH), are abnormally activated in colorectal cancer (CRC) samples. HERVH knockdown in colorectal cancer cell lines of high expression level of HERVH can lead to reduced cell proliferation and increased apoptosis. Meanwhile, the depression and apoptosis of organoid growth caused by HERVH knockdown can be observed through organoids generated from patient with rectal adenocarcinoma, suggesting that the survival of colorectal cancer cells are dependent on HERVH. Mechanistically, activation of HERVH is associated with the mutations of several tumor suppressors. Knockout of ARID1A in CRC cells leads to increased transcription at several HERVH loci, which involves compensatory contribution by ARID1B. Suppression of HERVH in CRC cells and patient-derived organoids impairs tumor growth. Altogether, the study uncover a critical role for ARID1A in restraining HERVH, whose abnormal activation can promote tumorigenesis by stimulating BRD4-dependent transcription, suggesting that HERVH may be a potential target for the treatment of colorectal cancer. The relevant findings have applied for invention patent.
Link to the article: https://doi.org/10.1038/s41467-022-31197-4
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