Oncogenic B-Raf proto-oncogene, serine/threonine kinase-mediated hedgehog signalling in the pathogenesis and targeted therapy of melanoma

Abstract

Melanoma is an aggressive type of skin cancer notorious for its resistance to chemotherapy, radiotherapy and immunotherapy, which greatly impacts its lethality. The hedgehog (HH) signaling cascade, originally known for its roles in embryonic development, regulates growth, proliferation and cancer stem cell (CSC) self-renewal. The glioma-associated oncogene homolog (GLI) transcription factors play crucial roles in melanoma. However, oncogenic B-Raf proto-oncogene, serine/threonine kinase (BRAF) steals the spotlight by driving the aberrant activation of HH-GLI1/2 signaling. Oncogenic BRAF-driven HH-GLI1/2 signaling imparts invasive phenotype to melanoma cells and sustains CSC self-renewal. Interestingly, the transcriptional activities of GLI1 and GLI2 are suppressed by acetylation, a process that is counteracted by the deacetylating actions of histone deacetylase (HDAC) 1/2. Therefore, inhibiting HDAC1/2 might keep GLI proteins in inactive acetylated form, thus representing an attractive druggable target. Notably, both HDAC1 and HDAC2 are induced by HH signaling, creating a positive feedback loop where HH signaling upregulates the expression of both HDAC1 and HDAC2. Selective inhibition of BRAF/HH/HDAC/GLI signaling axis is likely to unravel new therapeutic opportunities in melanoma. However, the precise contribution of oncogenic BRAF-driven HH signaling to therapy resistance and CSC renewal remains unclear and requires thorough investigation. In this article, we endeavored to explore the crosstalk between oncogenic BRAF and HH signaling, and the pivotal role this interaction plays in the self-renewal of melanoma stem cells. A better understanding of the molecular mechanisms governing these interactions is essential for improving melanoma treatment strategies and identifying new therapeutic targets.

Keywords: Melanoma; Hedgehog signaling; Acetylation; Mutations; Stem cells; Glioma-associated oncogene homolog; Targeted therapy

Core Tip: Oncogenic B-Raf proto-oncogene, serine/threonine kinase activates the hedgehog signaling pathway, triggering glioma-associated oncogene homolog (GLI) 1/2 transcription factors that promote melanoma cell invasion and sustain cancer stem cell self-renewal, contributing to the malignancy’s therapeutic resistance. Histone deacetylases 1/2 (HDAC1/2) suppress the acetylation of GLI1/2, facilitating their activation. Inhibiting HDAC1/2 may stabilize GLI proteins in their inactive, acetylated form, offering a novel approach to inhibit melanoma progression. Hedgehog signaling induces HDAC1/2 expression, creating a feedback loop that amplifies GLI-mediated transcription, promoting cancer stem cell renewal. Disrupting this loop could unveil new therapeutic avenues for overcoming melanoma’s resistance to treatment.