HDAC10 blockade upregulates SPARC expression thereby repressing melanoma cell growth and BRAF inhibitor resistance

Abstract

Secreted Protein Acidic and Rich in Cysteine (SPARC), a highly conserved secreted glycoprotein, is crucial for various bioprocesses. Here we demonstrate that histone deacetylase 10 (HDAC10) is a key regulator of SPARC expression. HDAC10 depletion or inhibition upregulates, while overexpression of HDAC10 downregulates, SPARC expression. Mechanistically, HDAC10 coordinates with histone acetyltransferase p300 to modulate the acetylation state of histone H3 lysine 27 (H3K27ac) at SPARC regulatory elements and the recruitment of bromodomain-containing protein 4 (BRD4) to these regions, thereby tuning SPARC transcription. HDAC10 depletion and resultant SPARC upregulation repress melanoma cell growth, primarily by induction of autophagy via activation of AMPK signaling. Moreover, SPARC upregulation due to HDAC10 depletion partly accounts for the resensitivity of resistant cells to a BRAF inhibitor. Our work reveals the role of HDAC10 in gene regulation through epigenetic modification and suggests a potential therapeutic strategy for melanoma or other cancers by targeting HDAC10 and SPARC. HighlightsO_LIHDAC10 is the primary HDAC member that tightly controls SPARC expression. C_LIO_LIHDAC10 coordinates with p300 in modulating the H3K27ac state at SPARC regulatory elements and the recruitment of BRD4 to these regions. C_LIO_LIHDAC10 depletion and resultant SPARC upregulation inhibit melanoma cell growth by inducing autophagy via activation of AMPK signaling. C_LIO_LISPARC upregulation as a result of HDAC10 depletion resensitizes resistant cells to BRAF inhibitors. C_LI