Increased CHST15 follows decline in arylsulfatase B (ARSB) and disinhibition of non-canonical WNT signaling: potential impact on epithelial and mesenchymal identity

Abstract

Expression of CHST15 (carbohydrate sulfotransferase 15; chondroitin 4-sulfate-6-sulfotransferase; BRAG), the sulfotransferase enzyme that adds 6-sulfate to chondroitin 4-sulfate (C4S) to make chondroitin 4,6-disulfate (chondroitin sulfate E, CSE), was increased in malignant prostate epithelium obtained by laser capture microdissection and following arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) silencing in human prostate epithelial cells. Experiments in normal and malignant human prostate epithelial and stromal cells and tissues, in HepG2 cells, and in the ARSB-null mouse were performed to determine the pathway by which CHST15 expression is up-regulated when ARSB expression is reduced. Effects of Wntcontaining prostate stromal cell spent media and selective inhibitors of WNT, JNK, p38, SHP2, β-catenin, Rho, and Rac-1 signaling pathways were determined. Activation of WNT signaling followed declines in ARSB and Dickkopf WNT Signaling Pathway Inhibitor (DKK)3 and was required for increased CHST15 expression. The increase in expression of CHST15 followed activation of non-canonical WNT signaling and involved Wnt3A, Rac-1 GTPase, phospho-p38 MAPK, and nuclear DNA-bound GATA-3. Inhibition of JNK, Sp1, β-catenin nuclear translocation, or Rho kinase had no effect. Consistent with higher expression of CHST15 in prostate epithelium, disaccharide analysis showed higher levels of CSE and chondroitin 6-sulfate (C6S) disaccharides in prostate epithelial cells. In contrast, chondroitin 4-sulfate (C4S) disaccharides were greater in prostate stromal cells. CSE may contribute to increased C4S in malignant epithelium when GALNS (N-aceytylgalactosamine-6-sulfate sulfatase) is increased and ARSB is reduced. These effects increase chondroitin 4-sulfates and reduce chondroitin 6-sulfates, consistent with enhanced stromal characteristics and epithelial-mesenchymal transition.

Subcellular Expression of Maspin in Colorectal Cancer: Friend or Foe

“…ARSB is directly correlated with maspin IHC expression, as an indicator of high invasive potential [37]. On the other hand, ARSB gene can inhibit the non-canonical Wnt signaling pathway and subsequently the EMT phenomenon via chondroitin 4-sulfate [36]. In line to these data, we previously proved that a low circulating level of ARSB gene (<0.5) is associated with double ARSB/maspin positivity of tumor cells and high grade of tumor budding [37], probably as an indicator of EMT [36,37].…”

“…Maspin nuclear expression could indicate a higher grade of dedifferentiation, especially in the invasive front, particularly for high-budding degree CRCs with microsatellite stable status (MSS) [11,28,[34][35][36]. It is expressed from early carcinogenesis up to advanced stage carcinomas with unresectable metastases [28,34].…”

“…In CRC, EMT mainly occurs via Wnt/β-catenin pathway which might interact with proteins such a mena (mammalian Ena homolog), arylsulfatase B (ARSB) or maspin [36][37][38]. ARSB is directly correlated with maspin IHC expression, as an indicator of high invasive potential [37].…”

“…As tumor lymphangiogenesis via maspin seems to be rather modulated by VEGF-C and its receptors VEGF-R2 and VEGF-R3 [14] and by the Hipoxia-inducing factor (HIF-1α) [62], while systemic metastases mainly occur via VEGF-A [63,64], the maspin-based tumor therapeutics should target these specific molecular endpoints. Moreover, due to the existing link between Wnt signaling pathway, ARSB, maspin and angiogenesis [36,65], a simultaneous inhibition of angiogenesis, tumor cell metabolism and EMT might be obtained through maspin modulation targeted therapy [37].…”

Molecular environment and atypical function: What do we know about enzymes associated with Mucopolysaccharidoses?

“…Increasement of chondroitin 4, 6-disulfate reduces the activity of SHP2 and re-activates Wnt signaling pathway (Fig. 2 ) ( 64 ). As a proto-oncogene, GALNS should be noticed during treatment for MPS IVA patients due to their impact on Wnt signaling pathway.…”