Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness

Tadijan, Ana; Precazzini, Francesca; Hanžić, Nikolina; Radić, Martina; Gavioli, Nicolo; Vlašić, Ignacija; Ozretić, Petar; Pinto, Lia; Škreblin, Lidija; Barban, Giulia; Slade, Neda; Ciribilli, Yari (2021) Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness. Cancers, 13 (20). ISSN 2072-6694

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Abstract

Cutaneous melanoma is the most aggressive form of skin cancer. Despite the significant advances in the management of melanoma in recent decades, it still represents a challenge for clinicians. The TP53 gene, the guardian of the genome, which is altered in more than 50% of human cancers, is rarely mutated in melanoma. More recently, researchers started to appreciate the importance of shorter p53 isoforms as potential modifiers of the p53-dependent responses. We analyzed the expression of p53 and p73 isoforms both at the RNA and protein level in a panel of melanoma-derived cell lines with different TP53 and BRAF status, in normal conditions or upon treatment with common anti-cancer DNA damaging agents or targeted therapy. Using lentiviral vectors, we also generated stable clones of H1299 p53 null cells over-expressing the less characterized isoforms Δ160p53α, Δ160p53β, and Δ160p53γ. Further, we obtained two melanoma-derived cell lines resistant to BRAF inhibitor vemurafenib. We observed that melanoma cell lines expressed a wide array of p53 and p73 isoforms, with Δ160p53α as the most variable one. We demonstrated for the first time that Δ160p53α, and to a lesser extent Δ160p53β, can be recruited on chromatin, and that Δ160p53γ can localize in perinuclear foci ; moreover, all Δ160p53 isoforms can stimulate proliferation and in vitro migration. Lastly, vemurafenib-resistant melanoma cells showed an altered expression of p53 and p73 isoforms, namely an increased expression of potentially pro-oncogenic Δ40p53β and a decrease in tumor-suppressive TAp73β. We therefore propose that p53 family isoforms can play a role in melanoma cells’ aggressiveness.

Item Type:	Article
Uncontrolled Keywords:	melanoma ; p53 ; p73 ; Δ160p53 ; isoforms ; targeted therapy ; resistance
Subjects:	NATURAL SCIENCES > Biology
Divisions:	Division of Molecular Medicine
Projects:	Project title Project leader Project code Project type Otkrivanje novih proteinskih interakcija kao podloga za nove pristupe liječenju melanoma čovjeka Slade, Neda IP-2013-11-1615 HRZZ
Depositing User:	Kristina Ciglar
Date Deposited:	07 Apr 2022 12:35
URI:	http://fulir.irb.hr/id/eprint/7223
DOI:	10.3390/cancers13205231

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