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Lysyl oxidase-like 2 (LOXL2) is a member of the scavenger receptor cysteine-rich (SRCR) repeat carrying LOX family. Although LOXL2 is suspected to be involved in histone association and chromatin modification, the role of LOXL2 in epigenetic regulation during tumorigenesis and cancer progression remains unclear. Here, we report that nuclear LOXL2 associates with histone H3 and catalyzes H3K36ac deacetylation and deacetylimination. Both the N-terminal SRCR repeats and the C-terminal catalytic domain of LOXL2 carry redundant deacetylase catalytic activity. Overexpression of LOXL2 markedly reduced H3K36 acetylation and blocked H3K36ac-dependent transcription of genes, including c-MYC, CCND1, HIF1A, and CD44. Consequently, LOXL2 overexpression reduced cancer cell proliferation in vitro and inhibited xenograft tumor growth in vivo. In contrast, LOXL2 deficiency resulted in increased H3K36 acetylation and aberrant expression of H3K36ac-dependent genes involved in multiple oncogenic signaling pathways. Female LOXL2-deficient mice spontaneously developed uterine hypertrophy and uterine carcinoma. Moreover, silencing LOXL2 in cancer cells enhanced tumor progression and reduced the efficacy of cisplatin and anti-programmed cell death 1 (PD-1) combination therapy. Clinically, low nuclear LOXL2 expression and high H3K36ac levels corresponded to poor prognosis in uterine endometrial carcinoma patients. These results suggest that nuclear LOXL2 restricts cancer development in the female reproductive system via the regulation of H3K36ac deacetylation. Significance: LOXL2 loss reprograms the epigenetic landscape to promote uterine cancer initiation and progression and repress the efficacy of anti–PD-1 immunotherapy, indicating that LOXL2 is a tumor suppressor.

Aberrant EGFR signaling is a common driver of glioblastoma (GBM) pathogenesis; however, the downstream effectors that sustain this oncogenic pathway remain unclarified. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM. EGFR signaling led to TRIM59 upregulation through SOX9 and enhanced the interaction between TRIM59 and nuclear STAT3, which prevents STAT3 dephosphorylation by the nuclear form of T-cell protein tyrosine phosphatase (TC45), thereby maintaining transcriptional activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumor formation of GBM cells and glioma stem cells. Evaluation of GBM patient samples revealed an association between EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR/STAT3 signaling and as a potential therapeutic target for GBM patients with EGFR activation. Significance: These findings identify a novel component of the EGFR/STAT3 signaling axis in the regulation of glioma tumorigenesis. Cancer Res; 78(7); 1792–804. ©2018 AACR.

Transcription factor Wilms' tumor 1 (WT1) was originally identified as a tumor suppressor for Wilms' tumor, but it is also overexpressed in a variety of cancer cells, suggesting a potential oncogenic function of WT1. It is important to understand molecular mechanisms underlying these dual functions of WT1 in tumorigenesis. In the current study, we report a synergistic role for signal transducers and activators of transcription 3 (STAT3) and WT1 in tumor development, including Wilms' tumor. STAT3 interacts with WT1 through its conserved domains both in vitro and in vivo. When STAT3 is activated, expression of WT1 enhances STAT3 transcriptional activity. Overexpression of WT1 and STAT3CA in NIH 3T3 increases the expression level of STAT3 target genes, including cyclin D1 and Bcl-xL, which results in an advantage of cell proliferation. Our results suggest that in the presence of activated STAT3, WT1 promotes cell proliferation instead of suppressing cell proliferation. Strikingly, STAT3 translocates to the nucleus and interacts with WT1 in a variety of primary Wilms' tumor cells, raising the hypothesis that WT1 and activated STAT3 in Wilms' tumor accelerate tumorigenesis. (Cancer Res 2006; 66(16): 8049-57)

Receptor protein-tyrosine kinases (RPTKs) are tightly regulated during normal cellular processes including cell growth, differentiation, and metabolism. Recently, a RPTK-like molecule named novel oncogene with kinase-domain (NOK) has been cloned and characterized. Overexpression of NOK caused severe cellular transformation as well as tumorigenesis and metastasis in nude mice. In the current study, we generated two tyrosine→phenylalanine (Y→F) point mutations (Y327F and Y356F) within the endodomain of NOK that are well conserved in many RPTK subfamilies and are the potential tyrosine phosphorylation sites important for major intracellular signaling. Using BaF3 cells stably expressing the ectodomain of mouse erythropoietin receptor, and the transmembrane and endodomain of NOK (BaF3-E/N), we were able to show that point mutations at either Y327 or Y356 dramatically blocked cellular transformation by NOK as examined by colony formation and cellular DNA synthesis. In addition, tumorigenesis induced by BaF3-E/N was completely abrogated upon the introduction of either single mutation. Importantly, signaling studies revealed that the activation of extracellular signal-regulated kinase was inhibited by Y356F and was significantly reduced by Y327F. Both mutations significantly impaired Akt phosphorylation. Interestingly, both mutations did not affect the kinase activity of NOK. Moreover, apoptotic analysis revealed that both mutations accelerated cell death by activating caspase-3–mediated pathways. Thus, our study shows that these potential tyrosine phosphorylation sites may play critical roles in NOK-mediated tumorigenesis both in vitro and in vivo.

Receptor protein tyrosine kinases (RPTKs) play important roles in the regulation of a variety of cellular processes including cell migration, proliferation, and protection from apoptosis. Here, we report the identification and characterization of a novel RPTK-like molecule that has a critical role in induction of tumorigenesis and metastasis and is termed Novel Oncogene with Kinase-domain (NOK). NOK contains a putative single transmembrane domain and a conserved intracellular tyrosine kinase domain that shares homology with members of the platelet-derived growth factor/fibroblast growth factor receptor superfamily. NOK was exclusively located in the cytoplasm. NOK mRNAs were detected in limited human organs and expressed with the highest abundance in the prostate. A variety of tumor cells also expressed the NOK mRNAs. We demonstrated that NIH3T3 and BaF3 cells could be strongly transformed by the expression of the NOK gene as examined by colony formation experiment. In addition, BaF3 cells with the stable expression of NOK induced rapid tumorigenesis in nude mice. Interestingly, these NOK-expressing tumor cells could promptly invade and spread into various distinct organs and form metastatic foci, eventually leading to the rapid death of these animals. Moreover, molecular mechanism studies indicated that NOK could concomitantly activate both MAP kinase and phosphatidylinositol 3′-kinases (PI3K) pathways in stable BaF3 cells. Thus, our results both in vitro and in vivo suggest that NOK is a novel oncogene with the capacity of promoting cell transformation, tumorigenesis, and metastasis.