Programmed cell death 11 modulates but not entirely relies on p53-HDM2 loop to facilitate G2/M transition in colorectal cancer cells

We previously described a nucleolar protein RSL1D1 but distributed throughout the nucleus in HCT116 colorectal cancer (CRC) cells to facilitate G1/S transition by inhibiting p53 signaling. Here, we found another nucleolar protein, programmed cell death 11 (PDCD11), also with an Extra-nucleolar localization in CRC cells but to regulate G2/M checkpoint. This protein directly interacts with p53 and HDM2 in the nucleoplasm, thereby recruiting p53 to HDM2 for ubiquitination and degradation. The ensuing downregulation of p53 increases the CDK1 level to help the cells pass G2/M checkpoint. Upon DNA damage stress, PDCD11 gains the power to upregulate CDK1 independently of p53. Beyond these, PDCD11 also upregulates CDC25C in a p53-independent manner to dephosphorylate CDK1 to facilitate G2/M transition. Downregulation of PDCD11 greatly reduced cancer cell growth in vitro and in vivo, additionally sensitized cells to DNA damage signals, highlighting that PDCD11 is a crucial driving factor of CRC and a potential target for cancer treatment.

Automated summary

This study reveals that PDCD11, a nucleolar protein, has an extra-nucleolar localization and regulates the G2/M checkpoint in colorectal cancer cells. PDCD11 interacts with p53 and HDM2 to facilitate p53 degradation, leading to downregulation of p53 and upregulation of CDK1 for G2/M transition. PDCD11 also independently upregulates CDC25C to dephosphorylate CDK1. Downregulation of PDCD11 inhibits cancer cell growth and increases sensitivity to DNA damage signals, suggesting its importance as a driving factor and potential target for colorectal cancer treatment.