TIP60 mediated regulation of ΔNp63α is associated with Cisplatin resistance

• Published in: The FASEB journal Vol. 36 Suppl 1
• Main Authors: Hira, Akshay, Stacy, Andrew J, Craig, Michael, Zhang, Jin, Kadakia, Madhavi
• Format: Journal Article
• Language: English
• Published: United States 01.05.2022
• ISSN: 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.R3273

About 5.4 million basal and squamous cell skin cancers are diagnosed each year in the US. Cisplatin, a chemotherapeutic drug is often used to treat squamous cell carcinoma (SCC) patients. However, 55% of cancers fail to respond leading to lower response rates and higher rates of disease re-occurrence. ΔNp63α a member of the p53 transcription factor family is overexpressed and considered oncogenic in non-melanoma skin cancer where it regulates cell survival and proliferation. TIP60 (Tat-interacting protein 60kDa), a histone acetyltransferase has been shown to mediate cellular processes such as transcription regulation and the DNA damage response (DDR). We recently reported that TIP60 positively regulates ΔNp63α protein levels in a catalytic-dependent manner to promote SCC proliferation. Since ΔNp63α is known to transcriptionally regulate several DDR genes and promote resistance to cisplatin, its stabilization by TIP60 may contribute to the failure of platinum-based drugs in SCC. We hypothesis that TIP60 mediated acetylation of ΔNp63α regulates its transcriptional activity thereby modulates chemoresistance. In this study, we showed that silencing of endogenous TIP60 in multiple SCC cell lines led to decrease in ΔNp63α transcript and protein levels confirming that TIP60 positively regulates ΔNp63α. Increased levels of TIP60 positively correlated with increased ΔNp63α expression and contributes to cisplatin resistance. Further, stable expression of TIP60 or ΔNp63α individually promoted resistance to cisplatin and reduced cell death, whereas loss of ΔNp63α and TIP60 sensitized cells to cisplatin. Higher acetylation of ΔNp63α and TIP60 were seen in cisplatin resistant cell line. Taken together, our data suggest that TIP60-mediated stabilization of ΔNp63α increases cisplatin resistance and has potential implication for SCC cancer treatment and drug design. Additionally, since ΔNp63α confers cisplatin resistance through regulation of genes involved in DNA damage repair, our findings provide critical insights into the mechanism by which genes involved in chemoresistance are regulated and may lead to strategic treatment for resistant SCC tumors and other epithelial cancers with increased efficacy.