KMT9 controls stemness and growth of colorectal cancer.
Christopher BerlinFelicie CottardDominica WillmannSylvia UrbanStephan M TirierLisa MarxKarsten RippeMark SchmittValentina PetrocelliFlorian R GretenStefan Fichtner-FeiglRebecca KesselringEric MetzgerRoland SchülePublished in: Cancer research (2021)
Colorectal cancer (CRC) is among the leading causes of cancer-associated deaths worldwide. Treatment failure and tumor recurrence due to survival of therapy-resistant cancer stem/initiating cells represent major clinical issues to overcome. In this study, we identified lysine methyltransferase 9 (KMT9), an obligate heterodimer composed of KMT9α and KMT9β that monomethylates histone H4 at lysine 12 (H4K12me1), as an important regulator in colorectal tumorigenesis. KMT9α and KMT9β were overexpressed in CRC and colocalized with H4K12me1 at promoters of target genes involved in the regulation of proliferation. Ablation of KMT9α drastically reduced colorectal tumorigenesis in mice and prevented the growth of murine as well as human patient-derived tumor organoids. Moreover, loss of KMT9α impaired the maintenance and function of CRC stem/initiating cells and induced apoptosis specifically in this cellular compartment. Together, these data suggest that KMT9 is an important regulator of colorectal carcinogenesis, identifying KMT9 as a promising therapeutic target for the treatment of CRC.
Keyphrases
- induced apoptosis
- endoplasmic reticulum stress
- signaling pathway
- oxidative stress
- endothelial cells
- cell cycle arrest
- type diabetes
- squamous cell carcinoma
- insulin resistance
- machine learning
- papillary thyroid
- cell death
- skeletal muscle
- combination therapy
- deep learning
- cancer stem cells
- pi k akt
- amino acid
- catheter ablation
- wild type
- pluripotent stem cells