• Role of CARM1 (PRMT4) in high grade serous ovarian cancer metabolism and function of PRMT5 in ARID1A- deficient endometrial cancer invasion
  • Lombardi, Simona <1995>

Subject

  • BIO/18 Genetica

Description

  • The arginine methyltransferase CARM1 (PRMT4) is amplified and overexpressed in ~20% of high-grade serous ovarian cancer (HGSOC) and correlates with a poor survival. Therapeutic approaches based on CARM1 expression remain to be an unmet need. Here we show that fatty acid metabolism represents a metabolic vulnerability for HGSOC in a CARM1 expression status dependent manner. CARM1 promotes the de novo synthesis of fatty acids and monounsaturated fatty acids (MUFAs). The disruption of MUFAs synthesis by inhibition of SCD1 results in excessive accumulation of cytotoxic saturated fatty acids and it is synthetic lethal with CARM1 expression. Collectively, our data show that the pharmacological inhibition of MUFAs synthesis via SCD1 inhibition represents a therapeutic strategy for CARM1-high HGSOC. Another arginine methyltransferase, PRMT5, has been identified by our CRISPR screening analysis as a promising candidate for invasive ARID1A-deficient endometrial cancer. Endometrial Cancer frequently harbor somatic inactivating mutation of ARID1A that can promote an invasive phenotype. Our in vitro approach validated the CRISPR screening showing that both PRTM5 knock down and its pharmaceutical inhibition specifically hamper the invasion of ARID1A inactivated cells. Mechanistically, PRMT5 directly regulates the epithelia to mesenchymal transition pathway genes interacting with the SWI/SNF complexes. Moreover, in vivo experiments showed that PRMT5 inhibition contrasted the myometrium invasion highlighting PRMT5 inhibition as promising therapeutic strategy for ARID1A- inactivated aggressive endometrial cancer.

Date

  • 2024-04-08
  • info:eu-repo/date/embargoEnd/2025-01-25

Type

  • Doctoral Thesis
  • PeerReviewed

Format

  • application/pdf

Identifier

http://amsdottorato.unibo.it/11121/1/Lombardi_Simona_tesi.pdf

urn:nbn:it:unibo-29961

Lombardi, Simona (2024) Role of CARM1 (PRMT4) in high grade serous ovarian cancer metabolism and function of PRMT5 in ARID1A- deficient endometrial cancer invasion, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Biologia cellulare e molecolare , 36 Ciclo.

Relations

http://amsdottorato.unibo.it/11121/