Phospho-ΔNp63α is a key regulator of the cisplatin-induced microRNAome in cancer cells

Abstract

Head and neck squamous cell carcinoma (HNSCC) cells exposed to cisplatin (CIS) displayed a dramatic ATM-dependent phosphorylation of DNp63a that leads to the transcriptional regulation of downstream mRNAs. Here, we report that phospho (p)-DNp63a transcriptionally deregulates miRNA expression after CIS treatment. Several p-DNp63a-dependent microRNA species (miRNAs) were deregulated in HNSCC cells upon CIS exposure, including miR-181a, miR-519a, and miR-374a (downregulated) and miR-630 (upregulated). Deregulation of miRNA expression led to subsequent modulation of mRNA expression of several targets (TP53-S46, HIPK2, ATM, CDKN1A and 1B, CASP3, PARP1 and 2, DDIT1 and 4, BCL2 and BCL2L2, TP73, YES1, and YAP1) that are involved in the apoptotic process. Our data support the notion that miRNAs are critical downstream targets of p-DNp63a and mediate key pathways implicated in the response of cancer cells to chemotherapeutic drugs.

Phospho-ΔNp63α/microRNA network modulates epigenetic regulatory enzymes in squamous cell carcinomas

“…36 We have further showed that the specific microRNAs downregulated or upregulated in SCC cells in response to cisplatin treatment are involved in a broad plethora of cellular processes, including apoptosis, autophagy, and various metabolic and signaling pathways. 36-39 P-ΔNp63α was also shown to transcriptionally activate or repress the specific microRNA promoters depending on the chromatin components bound to this transcriptional factor in SCC cells upon cisplatin exposure. 28 In this report, we continue our quest to understand the role of the cisplatin-induced TP63-regulated microRNAs in epigenetic regulation and chemoresistance.…”

“…34 We have also shown that the phosphorylated (p)-ΔNp63α protein is critical for the transcriptional regulation of downstream mRNAs and microRNAs in SCC cells upon cisplatin exposure. 35,36 Moreover, we have reported that p-ΔNp63α regulates microRNA expression in cisplatin-treated SCC cells through both transcriptional and post-transcriptional mechanisms. 36 We have further showed that the specific microRNAs downregulated or upregulated in SCC cells in response to cisplatin treatment are involved in a broad plethora of cellular processes, including apoptosis, autophagy, and various metabolic and signaling pathways.…”

“…35,36 Moreover, we have reported that p-ΔNp63α regulates microRNA expression in cisplatin-treated SCC cells through both transcriptional and post-transcriptional mechanisms. 36 We have further showed that the specific microRNAs downregulated or upregulated in SCC cells in response to cisplatin treatment are involved in a broad plethora of cellular processes, including apoptosis, autophagy, and various metabolic and signaling pathways. 36-39 P-ΔNp63α was also shown to transcriptionally activate or repress the specific microRNA promoters depending on the chromatin components bound to this transcriptional factor in SCC cells upon cisplatin exposure.…”

Subpath analysis of each subtype of head and neck cancer based on the regulatory relationship between miRNAs and biological pathways

“…Studies revealed that miR-519A was downregulated by ΔNp63α in cancers (48), and overexpression of ΔNp63α was beneficial for HNSCC resistance to chemotherapy-induced cell death via inhibiting the transcription of TAp73b (49). One study found that the downregulation of ΔNp63α was a determinant of cellular response to DNA damage in HNSCC (50).…”

MicroRNA

“…[44][45][46] In SCC cells, cisplatin exposure phosphorylates ΔNp63α, which directly regulates the transcription of many miRNAs. 44 Among the direct targets, miR-181a, miR-519a, miR-374a and miR-630 has been shown to regulate autophagy-related proteins, 34 which suggests that miRNAs can modulate autophagy pathway at another translational level. A number of previous studies have reported the direct involvement of p53 in autophagy.…”