ABHD5 inhibits YAP-induced c-Met overexpression and colon cancer cell stemness via suppressing YAP methylation

Cancer stemness represents a major source of development and progression of colorectal cancer (CRC). c-Met critically contributes to CRC stemness, but how c-Met is activated in CRC remains elusive. We previously identified the lipolytic factor ABHD5 as an important tumour suppressor gene in CRC. Here, we show that loss of ABHD5 promotes c-Met activation to sustain CRC stemness in a non-canonical manner. Mechanistically, we demonstrate that ABHD5 interacts in the cytoplasm with the core subunit of the SET1A methyltransferase complex, DPY30, thereby inhibiting the nuclear translocation of DPY30 and activity of SET1A. In the absence of ABHD5, DPY30 translocates to the nucleus and supports SET1A-mediated methylation of YAP and histone H3, which sequesters YAP in the nucleus and increases chromatin accessibility to synergistically promote YAP-induced transcription of c-Met, thus promoting the stemness of CRC cells. This study reveals a novel role of ABHD5 in regulating histone/non-histone methylation and CRC stemness.


Reporting for specific materials, systems and methods
We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response. The minimal sample size n of cell and animal experiments were determined by explanatory variable k , n>=k+1. The human colon cancer tissue microarray purchased from Shanghai Outdo Biotech Co.,Itd. with 107 samples were used for correlation and survival analyses. The surgically resected tissues from two CRC patients for ex vivo sphere formation assay were collected from Fuling Central Hospital. Sample size was chosen based on our previous published work and preliminary studies.
No data were excluded.
All the experimental findings were reliably reproduced as validated by independent experiments and biological replicates. Data presented in the manuscript was performed using at least N=3 biological replicates.
Age-and sex-matched mice were assigned randomly to experimental and control groups. For both in vitro and in vivo experiments, cells were randomly assigned to experimental groups, or based on genotype and treatment conditions. The human colon cancer tissue microarray samples were grouped based on genotype. No additional randomization was applicable to the study.
There is no commonly misdentified lines in all these cell lines.
Mice were housed and bred at the Medical Research Center of Southwest Hospital in specific pathogen-free conditions. All animals were housed under a controlled temperature (22±2°C), humidity (55±5%) and a 12 light-dark cycle (light on 7 am) with free access to food and water.
Both male and female mice were used for analysis and quantification.
Six-to eight-week-old male NOD/SCID mice on the C57BL/6J background were purchased from the Chinese Academy of Sciences Shanghai SLAC Laboratory Animal Co. (SLACCAS, Shanghai, China) and acclimated for 4 days.
We have not used wild animals in this study.
No field collected samples were used in the study All animal experiments were approved by the Institutional Animal Care and Use Committee of the Third Military Medical University (Army Medical University) in accordance with the Guide for the Care and Use of Laboratory Animals.