Genetic screening for anticancer genes highlights FBLN5 as a synthetic lethal partner of MYC

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Ectopic overexpression of anticancer genes like TRAIL, PAR4, and ORCTL3 selectively eliminates tumor cells.
• Studying anticancer genes reveals mechanisms of cancer development and spread.
• Current anticancer gene discovery is often accidental.

Purpose of the Study:

• To systematically isolate novel human anticancer genes using a gain-of-function forward genetic screen.
• To identify new therapeutic targets for cancer treatment.
• To understand the mechanisms of action for novel anticancer genes.

Main Methods:

• A systematic, gain-of-function, forward genetic screen was employed in mammalian cells.
• Over 30,000 transcripts were screened, focusing on 377 cell death-inducing genes.
• FIBULIN-5 (FBLN5) was selected for detailed mechanistic studies, including gene expression profiling and pathway analysis.

Main Results:

• Sixteen novel anticancer genes were identified, including non-coding RNAs, protein-coding genes, and novel transcripts (e.g., ZNF436-AS1, SMLR1, TMEFF2, LINC01529, HYAL2, NEIL2, FBLN5, YPEL4, PHKA2-processed transcript).
• FIBULIN-5 (FBLN5) selectively inhibited MYC expression in transformed COS-7 cells but not in normal CV-1 cells.
• MYC was identified as a synthetic lethality partner of FBLN5; MYC-transformed cells underwent cell death upon FBLN5 transfection, while MYC knockdown in MCF-7 cells abrogated FBLN5-induced cell death.

Conclusions:

• The human genome harbors at least sixteen novel anticancer genes, including FIBULIN-5 (FBLN5).
• MYC acts as a synthetic lethality partner for FBLN5, highlighting a potential therapeutic vulnerability.
• These findings provide new targets and strategies for cancer therapy.