Organ-specific regulation of CHD1 by acute PTEN and p53 loss in mice

Area of Science:

• Oncology
• Cancer Genetics
• Molecular Biology

Background:

• Homozygous deletion of chromodomain helicase DNA binding protein 1 (CHD1) is frequent in prostate cancer.
• CHD1 is essential for prostate cancer cell survival upon loss of phosphatase and tensin homolog (PTEN).
• The PTEN-CHD1 genetic relationship in other solid tumors is not understood.

Purpose of the Study:

• To investigate the PTEN-CHD1 genetic and functional relationship in solid tumors beyond prostate cancer.
• To elucidate the mechanistic basis for cancer type-specific copy number alterations of PTEN and CHD1.

Main Methods:

• Utilized genetically engineered mouse models with inducible deletion of Pten and p53 in adult mice.
• Co-deleted Chd1 along with Pten and p53 to assess its impact on lethality and phenotypes.
• Analyzed Chd1 protein stability in various organs (prostate, lung, liver, kidney, colon, mammary) following Pten deletion.

Main Results:

• Inducible deletion of Pten and p53 triggered PI3K/Akt pathway activation, causing multi-organ failure and lethality.
• Co-deletion of Chd1 did not alter the lethality in the Pten/p53 mouse model.
• Chd1 protein was stabilized upon Pten deletion in prostate cancer cells, but not in other examined organs.

Conclusions:

• The PTEN-CHD1 dependency is specific to prostate cancer and does not extend to other solid tumors.
• Chd1 stabilization upon Pten loss in prostate provides mechanistic insight into PTEN and CHD1 copy number alterations.
• Findings highlight organ-specific functional interactions of frequently altered cancer genes.