The abrogation of the HOXB7/PBX2 complex induces apoptosis in melanoma through the miR‐221&222‐c‐FOS pathway

Abstract

Cutaneous melanoma is the fastest increasing cancer worldwide. Although several molecular abnormalities have been associated with melanoma progression, the underlying mechanisms are still largely unknown and few targeted therapies are under evaluation. Here we show that the HOXB7/PBX2 dimer acts as a positive transcriptional regulator of the oncogenic microRNA-221 and -222. In addition, demonstrating c-FOS as a direct target of miR-221&222, we identify a HOXB7/PBX2→miR-221&222 →c-FOS regulatory link, whereby the abrogation of functional HOXB7/PBX2 dimers leads to reduced miR-221&222 transcription and elevated c-FOS expression with consequent cell death. Taking advantage of the treatment with the peptide HXR9, an antagonist of HOX/PBX dimerization, we recognize miR-221&222 as effectors of its action, in turn confirming the HXR9 efficacy in the treatment of human melanoma malignancy, whilst sparing normal human melanocytes. Our findings, besides suggesting the potential therapeutic of HXR9 or its derivatives in malignant melanoma, suggest the disruption of the HOXB7/PBX2 complexes, miR-221&222 inhibition or even better their combination, as innovative therapeutic approaches.

The Widening Sphere of Influence of HOXB7 in Solid Tumors

“…Among these, the PBX family members appeared as preferential binding partners of HOXB7 in melanoma (19,20). Along these lines, Errico reported the activating role of the HOXB7/PBX2 complex on miR-221 and miR-222 transcription, supporting a model involving an intricate and reciprocal interplay between HOXB7, their cofactors and microRNAs (5). These two clustered microRNAs are highly upregulated in a variety of solid tumors.…”

“…To this end, a small cell permeable peptide (HXR9) has been shown to trigger apoptosis in different cancer cells, including melanoma, antagonizing the interaction between HOX and PBX proteins, and disrupting the binding of these proteins to DNA consensus sites (36). In this regard, the study of Errico and collaborators suggest that the direct inhibition of miR-221 and miR-222 by antagomiR treatment and/or the disruption of the HOXB7/PBX2 dimers might represent innovative approaches for translation into the clinical setting (5). …”

“…These two clustered microRNAs are highly upregulated in a variety of solid tumors. Specifically, in melanoma miR-221 and miR-222 enhance tumorigenicity by targeting, among many other molecules, p27Kip1, ETS-1, c-KIT receptor and c-FOS, thus leading to enhanced proliferation, dissemination, differentiation blockade and apoptosis reduction (5,21). …”

“…These cofactors are members of the three amino acid loop extension (TALE) family that includes PBX (PBX1, 2, 3 and 4), MEIS (MEIS1, 2, and 3) and PREP (PREP1 and 2) (4). An example of such cooperation is the HOXB7/PBX2-dependent up-regulation of miR-221 and -222 in human melanoma cell lines, where the requirement of PBX cofactors for HOXB7-dependent tumorigenesis was highlighted (5). …”

Cyclovirobuxinum D alleviates cardiac hypertrophy in hyperthyroid rats by preventing apoptosis of cardiac cells and inhibiting the p38 mitogen-activated protein kinase signaling pathway

“…Bcl-2 inhibits apoptosis, whereas bax promotes apoptosis, therefore, the ratio of bax/bcl-2 can be used to evaluate apoptosis. (23) c-Fos protein has been characterized as a dimerization partner for c-Jun, (24) which plays a causal role in the activation of apoptosis (25) and formation of a c-fos/c-jun complex contributes to cell apoptosis. (26) In the present study, changes in bcl-2 and bax protein expression in myocardial cells were determined by immunohistochemical analysis and c-fos and c-jun mRNA expression was determined by RT-qPCR.…”