TIP60 regulation of ΔNp63α is Associated with Cisplatin Resistance

About 5.4 million basal and squamous cell skin cancers are diagnosed every year in the US. ΔNp63a, a member of the p53 transcription factor family, is overexpressed in non-melanoma skin cancer and regulates cell survival, migration and invasion. TIP60 is histone acetyltransferase (HAT) which mediates cellular processes such as transcription and the DNA damage response (DDR). Previous studies in our lab have shown that overexpression of TIP60 induces ΔNp63a protein stabilization in a catalytic-dependent manner. Since ΔNp63a is known to transcriptionally regulate several DDR genes and promote cisplatin resistance, its stabilization by TIP60 may contribute to the failure of platinum-based drugs in squamous cell carcinoma (SCC). We hypothesize that TIP60 regulates the transcriptional activity of ΔNp63a thereby modulating chemoresistance. In this study, we showed that overexpression of TIP60 in both H1299 and A431 cells led to stabilization of ΔNp63α, while TIP60 silencing in A431 cell lines led to a decrease in endogenous ΔNp63α transcript and protein levels, thus confirming that TIP60 positively regulates ΔNp63α in these cell lines. Increased levels of ΔNp63a TIP60 correlated with increased ΔNp63a expression and contributed 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 ΔNp63a and TIP60 were seen cisplatin resistant cells. Taken together, our data suggest that TIP60-mediated stabilization of ΔNp63α increases cisplatin resistance and has potential implications for cancer treatment and drug design. Additionally, since ΔNp63α confers cisplatin resistance through regulation of genes involved in DNA damage repair, our findings provide critical insight into the mechanism by which genes involved in cisplatin resistance are regulated and may lead to strategies for treating resistant tumors with increased efficacy.https://corescholar.libraries.wright.edu/urop_celebration/1064/thumbnail.jp

Ileosigmoid knot: A case report

The ileosigmoid knot is an uncommon but life-threatening cause of closed loop intestinal obstruction. Its treatment is different from a simple volvulus in that it has to be operated upon immediately. Preoperative CT scan diagnosis and prompt treatment can lead to a good outcome. Findings of simultaneous ileal and sigmoid ischemia with non-ischemic colon interposed in between should, in an appropriate clinical setting, indicate this condition. The presence of the whirl sign, medially deviated distal descending colon and cecum, and mesenteric vascular structures from the superior mesenteric vessels that converge toward the sigmoid colon on CT scan help clinch the diagnosis

TIP60 regulation of ΔNp63α is Associated with Cisplatin Resistance

About 5.4 million basal and squamous cell skin cancers are diagnosed every year in the US. ΔNp63a, a member of the p53 transcription factor family, is overexpressed in non-melanoma skin cancer and regulates cell survival, migration and invasion. TIP60 is histone acetyltransferase (HAT) which mediates cellular processes such as transcription and the DNA damage response (DDR). Previous studies in our lab have shown that overexpression of TIP60 induces ΔNp63a protein stabilization in a catalytic-dependent manner. Since ΔNp63a is known to transcriptionally regulate several DDR genes and promote cisplatin resistance, its stabilization by TIP60 may contribute to the failure of platinum-based drugs in squamous cell carcinoma (SCC). We hypothesize that TIP60 regulates the transcriptional activity of ΔNp63a thereby modulating chemoresistance. In this study, we showed that overexpression of TIP60 in both H1299 and A431 cells led to stabilization of ΔNp63α, while TIP60 silencing in A431 cell lines led to a decrease in endogenous ΔNp63α transcript and protein levels, thus confirming that TIP60 positively regulates ΔNp63α in these cell lines. Increased levels of ΔNp63a TIP60 correlated with increased ΔNp63a expression and contributed 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 ΔNp63a and TIP60 were seen cisplatin resistant cells. Taken together, our data suggest that TIP60-mediated stabilization of ΔNp63α increases cisplatin resistance and has potential implications for cancer treatment and drug design. Additionally, since ΔNp63α confers cisplatin resistance through regulation of genes involved in DNA damage repair, our findings provide critical insight into the mechanism by which genes involved in cisplatin resistance are regulated and may lead to strategies for treating resistant tumors with increased efficacy

TIP60 Up-Regulates ΔNp63α to Promote Cellular Proliferation

An estimated 5.4 million cases of nonmelanoma skin cancer are reported in the United States at an associated cost of $4.8 billion. ΔNp63α, a proto-oncogene in the p53 family of transcription factors, is overexpressed in squamous cell carcinoma (SCC) and associated with poor prognosis and survival. ΔNp63α elicits its tumorigenic effects in part by promoting cellular proliferation and cell survival. Despite its importance in SCC, the upstream regulation of ΔNp63α is poorly understood. In this study, we identify TIP60 as a novel upstream regulator of ΔNp63α. Using a combination of overexpression, silencing, stable expression, and pharmacological approaches in multiple cell lines, we showed that TIP60 up-regulates ΔNp63α expression. Utilizing cycloheximide treatment, we showed that TIP60 catalytic activity is required for stabilization of ΔNp63α protein levels. We further showed that TIP60 coexpression inhibits ΔNp63α ubiquitination and proteasomal degradation. Stabilization of ΔNp63α protein was further associated with TIP60-mediated acetylation. Finally, we demonstrated that TIP60-mediated regulation of ΔNp63α increases cellular proliferation by promoting G2/M progression through MTS assays and flow cytometry. Taken together, our findings provide evidence that TIP60 may contribute to SCC progression by increasing ΔNp63α protein levels, thereby promoting cellular proliferation