Mutant p53 induces SH3BGRL expression to promote cell engulfment

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Mutant p53 (mutant p53) expression is prevalent in cancers and linked to gain-of-function (GOF) processes.
• Mutant p53 promotes cell-in-cell (CIC) structure formation, conferring tumor formation advantages.
• The specific mechanisms and genes involved in mutp53-driven CIC formation and associated GOFs are not fully understood.

Purpose of the Study:

• To identify genes regulated by mutant p53 that mediate cell engulfment.
• To investigate the role of SH3BGRL (Src homology 3 binding glutamate rich protein like) and cell engulfment in mutant p53-dependent anchorage-independent growth and chemoresistance.
• To elucidate the contribution of SH3BGRL and cell engulfment to mutant p53 GOFs.

Main Methods:

• Utilized Next Generation Sequencing (NGS) to identify novel mutant p53 target genes.
• Generated mutant p53 and p53 knockout (KO) cell lines with stable SH3BGRL overexpression.
• Employed Fluorescence-Activated Cell Sorting (FACS) to isolate pure cell-engulfing (CIC) populations.

Main Results:

• Identified SH3BGRL as a novel mutant p53-regulated gene essential for cell engulfment.
• Demonstrated that SH3BGRL promotes etoposide resistance in mutant p53 cells and anchorage-independent growth, independent of mutant p53.
• Confirmed enhanced etoposide resistance in purified CIC populations, highlighting the role of engulfment.

Conclusions:

• SH3BGRL is a key mediator of mutant p53-driven cell engulfment and CIC formation.
• SH3BGRL and the resulting cell engulfment process are critical for specific mutant p53 gain-of-function phenotypes, including chemoresistance and anchorage-independent growth.
• These findings provide new insights into the molecular mechanisms underlying mutant p53 oncogenic functions.