Decline in arylsulfatase B expression increases EGFR expression by inhibiting the protein-tyrosine phosphatase SHP2 and activating JNK in prostate cells

Abstract

Epidermal growth factor receptor (EGFR) has a crucial role in cell differentiation and proliferation and cancer, and its expression appears to be up-regulated when arylsulfatase B (ARSB or GalNAc-4-sulfatase) is reduced. ARSB removes 4-sulfate groups from the nonreducing end of dermatan sulfate and chondroitin 4-sulfate (C4S), and its decreased expression has previously been reported to inhibit the activity of the ubiquitous protein-tyrosine phosphatase, nonreceptor type 11 (SHP2 or PTPN11). However, the mechanism by which decline in ARSB leads to decline in SHP2 activity is unclear. Here, we show that SHP2 binds preferentially C4S, rather than chondroitin 6-sulfate, and confirm that SHP2 activity declines when ARSB is silenced. The reduction in ARSB activity, and the resultant increase in C4S, increased the expression of EGFR (Her1/ErbB1) in human prostate stem and epithelial cells. The increased expression of EGFR occurred after 1) the decline in SHP2 activity, 2) enhanced c-Jun N-terminal kinase (JNK) activity, 3) increased nuclear DNA binding by c-Jun and c-Fos, and 4) EGFR promoter activation. In response to exogenous EGF, there was increased bromodeoxyuridine incorporation, consistent with enhanced cell proliferation. These findings indicated that ARSB and chondroitin 4-sulfation affect the activation of an important dual phosphorylation threonine-tyrosine kinase and the mRNA expression of a critical tyrosine kinase receptor in prostate cells. Restoration of ARSB activity with the associated reduction in C4S may provide a new therapeutic approach for managing malignancies in which EGFR-mediated tyrosine kinase signaling pathways are active.

Dihydrotestosterone inhibits arylsulfatase B and Dickkopf Wnt signaling pathway inhibitor (DKK)‐3 leading to enhanced Wnt signaling in prostate epithelium in response to stromal Wnt3A

“…The resumption of normalized metabolic pathways and decline in proliferation might follow. However, additional mechanisms that lead to decline in ARSB, such as estrogen exposure or hypoxia, may contribute to reduction in ARSB and to the activation of pathways that contribute to proliferation, such as increased EGFR receptor expression . These may be bypass mechanisms that lead to unresponsiveness to androgen ablation .…”

“…Increases in chondroitin sulfate and the chondroitin sulfate proteoglycan versican were identified in more aggressive prostate cancers . Increased C4S has significant consequences for transcription, signaling, metabolism, and proliferation in the prostate and in other tissues …”

Distinct Effects of Carrageenan and High-Fat Consumption on the Mechanisms of Insulin Resistance in Nonobese and Obese Models of Type 2 Diabetes

“…Also, the increase in C4S when ARSB is reduced has been shown to lead to increased binding of C4S with SHP2, the nonmembrane tyrosine phosphatase (PTPN11). Increased binding of SHP2 with C4S when ARSB is reduced inhibited SHP2 phosphatase activity [38, 39]. This carrageenan-related effect may impact on the tyrosine phosphorylations of the insulin receptor and/or IRS-1 and impair the propagation of insulin signaling, due to sustained tyrosine phosphorylation.…”

Carrageenan-Free Diet Shows Improved Glucose Tolerance and Insulin Signaling in Prediabetes: A Randomized, Pilot Clinical Trial

“…We suggest that carrageenaninduced changes in ARSB and C4S may impact galectin-3 availability and contribute to the effect on HbA1c that we report. Also, in other works, a decline in ARSB led to increased C4S and increased binding of C4S with SHP2 (PTPN11), the ubiquitous nonreceptor tyrosine phosphatase [36][37][38]. Increased binding of SHP2 with C4S reduced SHP2 activity, leading to sustained phosphorylation of several mediators, including phospho-ERK1/2, phospho-JNK, and phospho-p38 MAPK.…”