Intense infiltration of tumour-associated macrophages (TAMs) facilitates malignant growth of glioblastoma (GBM), but the underlying mechanisms remain undefined. Herein, we report that TAMs secrete abundant pleiotrophin (PTN) to stimulate glioma stem cells (GSCs) through its receptor PTPRZ1 thus promoting GBM malignant growth through PTN–PTPRZ1 paracrine signalling. PTN expression correlates with infiltration of CD11b+/CD163+ TAMs and poor prognosis of GBM patients. Co-implantation of M2-like macrophages (MLCs) promoted GSC-driven tumour growth, but silencing PTN expression in MLCs mitigated their pro-tumorigenic activity. The PTN receptor PTPRZ1 is preferentially expressed in GSCs and also predicts GBM poor prognosis. Disrupting PTPRZ1 abrogated GSC maintenance and tumorigenic potential. Moreover, blocking the PTN–PTPRZ1 signalling by shRNA or anti-PTPRZ1 antibody potently suppressed GBM tumour growth and prolonged animal survival. Our study uncovered a critical molecular crosstalk between TAMs and GSCs through the PTN–PTPRZ1 paracrine signalling to support GBM malignant growth, indicating that targeting this signalling axis may have therapeutic potential.

The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer.

The histone deacetylase inhibitors (HDACIs) butyrate and trichostatin A activate ␥-globin expression via a p38 mitogenactivating protein kinase (MAPK)-dependent mechanism. We hypothesized that downstream effectors of p38 MAPK, namely activating transcription factor-2 (ATF-2) and cyclic AMP response element (CRE) binding protein (CREB), are intimately involved in fetal hemoglobin induction by these agents. In this study, we observed increased ATF-2 and CREB1 phosphorylation mediated by the HDACIs in K562 cells, in conjunction with histone H4 hyperacetylation. Moreover, enhanced DNAprotein interactions occurred in the CRE in the G ␥-globin promoter (G-CRE) in vitro after drug treatments; subsequent chromatin immunoprecipitation assay confirmed ATF-2 and CREB1 binding to the G-CRE in vivo. Enforced expression of ATF-2 and CREB produced G ␥-promoter IntroductionThe growth factor erythropoietin (Epo) exerts its effects on commitment, proliferation, and differentiation of erythroid progenitors and globin chain synthesis through Janus kinase 2/Stat5 signaling and crosstalk with mitogen-activated protein kinase (MAPK) pathways. 1-3 p38 MAPK signaling is required for Epo mRNA stability and hemoglobin synthesis. 4,5 The reversible inhibition of p38 MAPK using SB203580 blocked Epo-dependent accumulation of mouse globin chains, 6 and studies in p38␣ Ϫ/Ϫ knockout mice showed a failure of definitive ␤ maj -globin gene expression. These studies confirm an Epo-p38 MAPK-dependent mechanism for hemoglobin synthesis. 7 The HDACI sodium butyrate (NaB) induces differentiation in erythroleukemia cells via Stat5 8,9 and p38 MAPK signaling. 10,11 Butyrate is a clinically useful fetal hemoglobin (HbF) inducer which has been used to treat individuals with sickle cell disease 12 and thalassemia 13 ; however, the molecular mechanism for NaB-mediated HbF induction is poorly understood. Recent data from Weinberg et al 14 showed that HbF induction by arginine butyrate is due in part to posttranslational mechanisms and increased ␥-globin mRNAtranslation.Several HDACIs, including trichostatin A (TSA), 10, and scriptaid,15,16 induce ␥-globin expression via p38 MAPK signaling. These studies suggest that different pharmacologic agents converge on the p38 MAPK pathway to activate ␥-globin expression. Four major MAPK pathways have been characterized: ERK1/2, ERK5/BMK1, cJun amino-terminal signal kinases (JNK), and p38. [17][18][19][20] Studies using erythroid progenitors, 21,22 knockout mice, 7 and K562 stable lines 10 suggest that p38␣ is the primary mediator of globin gene regulation.The downstream effector molecules of p38 MAPK signaling include MAPK-activated protein kinases 1 and 2, 23,24 PRAK, 25 ATF-1-4, CREB1, CREB2, and CREM. 26,27 Commonly, p38 phosphorylates ATF-2 and CREB to augment gene transcription. We recently demonstrated a p38 MAPK-dependent mechanism for NaB and TSA-induced ␥-globin expression. 10 Mechanistically, both agents bind a central zinc atom in HDAC to produce hyperacetylation of histone H3 (H3) and H4 28,29 to activate...