Abstract
BMP4/7-dependent expression of inhibitor of differentiation/DNA binding (Id) proteins 1 and 3 has been implicated in tumor progression and poor prognosis of malignant melanoma patients. Hyaluronic acid (HA), a pericellular matrix component, supports BMP7 signalling in murine chondrocytes through its receptor CD44. However, its role in regulating BMP signalling in melanoma is not clear. In this study we found that depletion of endogenously-produced HA by hyaluronidase treatment or by inhibition of HA synthesis by 4-methylumbelliferone (4-MU) resulted in reduced BMP4/7-dependent Id1/3 protein expression in mouse melanoma B16-F10 and Ret cells. Conversely, exogenous HA treatment increased BMP4/7-dependent Id1/3 protein expression. Knockdown of CD44 reduced BMP4/7-dependent Id1/3 protein expression, and attenuated the ability of exogenous HA to stimulate Id1 and Id3 expression in response to BMP. Co-IP experiments demonstrated that CD44 can physically associate with the BMP type II receptor (BMPR) ACVR2B. Importantly, we found that coordinate expression of Id1 or Id3 with HA synthases HAS2, HAS3, and CD44 is associated with reduced overall survival of cutaneous melanoma patients. Our results suggest that HA-CD44 interactions with BMPR promote BMP4/7-dependent Id1/3 protein expression in melanoma, contributing to reduced survival in melanoma patients.
Highlights
BMP4/7-dependent expression of inhibitor of differentiation/DNA binding (Id) proteins 1 and 3 has been implicated in tumor progression and poor prognosis of malignant melanoma patients
In further experiments we found that the expression of Id1/3 proteins was increased by BMP4/7 stimulation in a dose-dependent manner (Supplementary Fig. S1A)
We show that degradation of Hyaluronic acid (HA) in the pericellular matrix or inhibition of endogenous HA synthesis reduces BMP4/7- dependent Id1/3 protein expression, while exogenous HA has the opposite effect
Summary
BMP4/7-dependent expression of inhibitor of differentiation/DNA binding (Id) proteins 1 and 3 has been implicated in tumor progression and poor prognosis of malignant melanoma patients. Bone morphogenetic proteins (BMPs) belong to the transforming growth factor β (TGF-β) superfamily They signal through specific type I and II serine/threonine receptors, which in turn activate Smad-1/5/8 transcription factors. The four members of the Id family (Id1-4) are helix-loop-helix proteins that lack a DNA-binding domain, and act as dominant-negative antagonists of basic helix-loop-helix transcription factors by forming inactive heterodimers[2] Through this activity Id proteins regulate a variety of cellular processes including proliferation, migration, invasion, angiogenesis, maintenance of stem cell properties, and cell differentiation[3,4]. Increased Id1 expression has been correlated with tumor progression and poor prognosis in malignant melanoma patients[16]. Hyaluronan (HA) is a linear high molecular weight polysaccharide in the ECM that is www.nature.com/scientificreports/
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