Y‐box Binding Protein‐1 Is Part of a Complex Molecular Network Linking ΔNp63α to the PI3K/akt Pathway in Cutaneous Squamous Cell Carcinoma

Abstract

Cutaneous squamous cell carcinomas (SCCs) typically lack somatic oncogene-activating mutations and most of them contain p53 mutations. However, the presence of p53 mutations in skin premalignant lesions suggests that these represent early events during tumor progression and additional alterations may be required for SCC development. SCC cells frequently express high levels of ΔNp63α and Y-box binding 1 (YB-1 or YBX1) oncoproteins. Here, we show that knockdown of YB-1 in spontaneously immortalized HaCaT and non-metastatic SCC011 cells led to a dramatic decrease of ΔNp63α, cell detachment and death. In highly metastatic SCC022 cells, instead, YB-1 silencing induces PI3K/AKT signaling hyperactivation which counteracts the effect of YB-1 depletion and promotes cell survival. In summary, our results unveil a functional cross-talk between YB-1, ΔNp63α and the PI3K/AKT pathway critically governing survival of squamous carcinoma cells.

ΔNp63α controls YB‐1 protein stability: evidence on YB‐1 as a new player in keratinocyte differentiation

“…) and YB‐1 increases ΔNp63 α mRNA and protein level (Troiano et al . ), our latest information indicates the existence of a reciprocal positive control between ΔNp63 α and YB‐1 as we have schematically represented in Fig. .…”

“…), whereas YB‐1 silencing induces apoptosis in mitotically active HaCaT keratinocytes (Troiano et al . ).…”

“…Interestingly, we have previously shown that YB‐1 silencing causes a reduction of ΔNp63 α level at mRNA and protein level (Troiano et al . ). A relevant issue to explore will be whether YB‐1 expression can exert a selective control on ΔNp63 α transcriptional functions and what might be the effect of mutant p63 on YB‐1 functions.…”

“…Recently, we have showed that YB‐1 silencing affects ΔNp63 α expression and viability of human immortalized keratinocytes (Troiano et al . ). Here, we showed evidence that ΔNp63 α controls YB‐1 protein stability suggesting that ΔNp63 α /YB‐1 cross talk is relevant for survival of basal keratinocytes in stratified epithelia.…”

Y-box-binding protein 1 contributes to IL-7-mediated survival signaling in B-cell precursor acute lymphoblastic leukemia

“…Phosphorylation of YB-1 S102 activates the translation of mRNA involved in growth and survival, while direct phosphorylation or subsequent stress induces nuclear localization enabling YB-1 to exert transcriptional control on a further subset of genes, including those involved in drug resistance (16,45). In contrast to results from studies on squamous carcinoma cells (46), reduced leukemia cell viability was not observed following YB-1 knockdown alone. The current study, however, implicates the activation of YB-1 by IL-7 as a mechanism contributing to the survival of BCP ALL in the presence of cytotoxic stressors.…”