Multiple genetic aberrations in the regulation of BCL6, including in acetyltransferase genes, occur in clinically aggressive B-cell lymphomas and lead to higher expression levels and activity of this transcriptional repressor. BCL6 is, therefore, an attractive target for therapy in aggressive lymphomas. In this study romidepsin, a potent histone deacetylase inhibitor (HDACi), induced apoptosis and cell cycle arrest in Burkitt and diffuse large B-cell lymphoma cell lines, which are model cells for studying the mechanism of action of BCL6. Romidepsin caused BCL6 acetylation at early timepoints inhibiting its function, while at later timepoints BCL6 expression was reduced and target gene expression increased due to chromatin modification. MYC contributes to poor prognosis in aggressive lymphoma. MYC function is reduced by inhibition of chromatin readers of the bromodomain and extra-terminal repeat (BET) family, which includes BRD4. The novel combination of romidepsin and JQ1, a BRD4 inhibitor was investigated and showed synergy. Collectively we suggest that the combination of HDACi and BRD4i should be pursued in further pre-clinical testing. Aggressive lymphomas such as diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) are a heterogeneous group of disorders in terms of clinical behavior, biological characteristics and response to treatments 1. Despite improvements in diagnosis and treatment, non-Hodgkins-lymphomas are still an important cause of morbidity and mortality worldwide. Combination of rituximab with anthracycline-based chemotherapy regimen, such as R-CHOP (Rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone) is effective 2 but overall >40% of patients are not cured of their disease. Thus, it is important to identify new approaches to therapy. Aggressive lymphomas are often derived from germinal center B-cells. Germinal centers are dynamic structures within normal lymph nodes, where B-cells proliferate intensely and undergo somatic hypermutation 3 , a process involving the production of DNA breaks that is essential for the formation of high affinity antibodies. Conditions within the germinal center are therefore believed to predispose to the formation of lymphomas 3. There is a wealth of genetic evidence that BCL6 contributes to the survival of DLBCL and clinical evidence suggests that a proportion of BCL6 expressing DLBCL patients have poor clinical outcomes. The role of BCL6 in Burkitt lymphoma has not been investigated but it is expressed in all cases and is likely to contribute to proliferation and survival. BCL6 is a master transcription factor that is essential for normal germinal center formation 4,5. Enforced expression of BCL6 in mice is sufficient for the development of lymphomas 6. Multiple genetic abnormalities

MNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix–loop–helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it. However, the molecular interactions involving MNT as a transcriptional regulator beyond the binding to MAX remain unexplored. Here we demonstrate a novel MAX-independent protein interaction between MNT and REL, the oncogenic member of the NF-κB family. REL participates in important biological processes and it is altered in a variety of tumors. REL is a transcription factor that remains inactive in the cytoplasm in an inhibitory complex with IκB and translocates to the nucleus when the NF-κB pathway is activated. In the present manuscript, we show that MNT knockdown triggers REL translocation into the nucleus and thus the activation of the NF-κB pathway. Meanwhile, MNT overexpression results in the repression of IκBα, a bona fide REL target. Both MNT and REL bind to the IκBα gene on the first exon, suggesting its regulation as an MNT–REL complex. Altogether our data indicate that MNT acts as a repressor of the NF-κB pathway by two mechanisms: (1) retention of REL in the cytoplasm by MNT interaction, and (2) MNT-driven repression of REL-target genes through an MNT–REL complex. These results widen our knowledge about MNT biological roles and reveal a novel connection between the MYC/MXD and NF-κB pathways, two of the most prominent pathways in cancer.

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MNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix-loop-helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it. However, the molecular interactions involving MNT as a transcriptional regulator beyond the binding to MAX remain unexplored. Here we demonstrate a novel MAX-independent protein interaction between MNT and c-REL (REL), the oncogenic member of the REL/NF-κB family. REL is involved in important biological processes and it is found altered in a variety of tumors. REL is a transcription factor that remains inactive in the cytoplasm in an inhibitory complex with IκB and translocates to the nucleus when the NF-κB pathway is activated. In the present manuscript, we show that MNT knockdown triggers REL translocation into the nucleus and thus the activation of the NF-κB pathway. Meanwhile, MNT overexpression results in the repression of IκBα, a bona-fide REL target. Indeed, both MNT and REL bind to the IκBα gene at a region mapping in the first exon, suggesting its regulation as a MNT-REL complex. Altogether our data indicate that MNT acts as a repressor of the NF-κB pathway by two different mechanisms: 1) retention of REL in the cytoplasm by MNT protein interaction and 2) MNT-driven repression of REL-target genes through a MNT-REL complex. These results widen our knowledge about MNT biological roles and reveal a novel connection between the MYC/MXD and the NF-κB pathways, two of the most prominent pathways involved in cancer.

Introduction Prostate cancer is the most common male cancer. Epidemiological research have shown that physical activity can reduce the mortality of prostate cancer, and we have previously shown that endurance training can increase PSA doubling time, as a surrogate of reduced cancer progression, in prostate cancer patients in active surveillance.The molecular basis of prostate cancer is not fully understood, but dysregulation of the androgen receptor (AR) is a key factor. Upstream of AR are traditional cancer-related factors including b-catenin, which is a core component of the Wnt pathway, and YAP, one of the main downstream effectors of the Hippo pathway. Recent research has shown that YAP/ TAZ is a central component of the b-catenin destruction complex thereby demonstrating a crosslink between the two pathways. Moreover, we have recently demonstrated that exerciseconditioned serum can activate Hippo signalling in breast cancer, thereby suppressing cancer cell viability. Material and methods We utilise the human prostate cancer cell lines (LNCaP and PC3) for the exercise-conditioned serum incubation experiments, using exercise-conditioned serum obtained from young healthy men who have completed 2 hours of biking. In these incubations, we have observed that post-exercise serum can reduce the viability of both LNCaP and PC3 cells with up to 10%. Results and discussions For this project we hypothesise that physical activity, due to exercise-induced catecholamines, activate the Hippo pathway, thereby restricting YAP/TAZ to the cytoplasm and keeping YAP/TAZ in the b-catenin destruction complex preventing gene transcription. This crosstalk between the Hippo-and Wnt pathway provide us with a mechanistic explanation for the inhibitory effect of physical activity on prostate cancer cell growth. Conclusion Physical activity may constitute a potential option for controlling and inhibiting prostate cancer cell growth, and the aim of this study is thus to get a more thoroughly understanding of how physical activity inhibits prostate cancer cell growth.

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