A novel p53 barrier destruction mechanism through MMP‐7 mediating nucleolar matrix assembly & intra‐nucleolar cleaving p53 during cancer stem cell transformation

Abstract

The molecular mechanism underlying the striking enlarged nucleolus instead of disperse small nucleolus in cancer stem cells remains elusive. Our novel findings that MUC‐1 C‐ter participates in nucleolus matrix assembly has further prompted the idea that the cell surface receptor MUC‐1, via MMP‐7 proteolytic cleavage of the MUC‐1 SEA domain releases cryptic bioactive fragments that orchestrate nucleolar activities. Furthermore, MUC‐1 C‐ter induces a unique porous bulky ball‐shaped, cage‐like nucleolus that functions as a nucleus molecular “garage”for potent transcription factors, such as γ‐catenin and p53. Specifically, this cage segregates the transcription factors from its target promoter. In addition, the intra nucleolus degradation of p53 by MMP‐7 to generate a 35 kDa p53 fragment suggests that the nucleolus could also facilitate the novel subnucleus compartment for proteolytic processing tumor suppressor protein, p53 in cancer stem like cell, which implicate the novel molecular mechanism for destructing the p53 barrier and inducing cancer stem cell transformation. Salinomycin, an anti‐cancer stem cell agent, can disrupt the nucleolus inducing translocation of p53 and sensitize cancer stem cell to chemotherapy drug. These data provide important new insights into the dysregulations of cancer stem cells as well as highlight targets for cancer therapeutics.Support or Funding InformationTaiwan Ministry of Science and technology 94‐2320‐B‐002 ‐120This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.