BCL9 provides multi-cellular communication properties in colorectal cancer by interacting with paraspeckle proteins

Meng Jiang,Helen Tanton,Amitabh Srivastava,Runsheng Chen,Zhongqiu Wang,Tomasz Sewastianik,Keith Alder,Jiao Wang,Massimo Loda,Ying Huang,Ming Liu,Yu Xin,Yue Kang,Ruiyang Liu,Mengyun Zhang,Ruben D Carrasco,Peter Dennis

doi:10.1038/s41467-019-13842-7

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed cancer, which despite recent advances in treatment, remains incurable due to molecular heterogeneity of tumor cells. The B-cell lymphoma 9 (BCL9) oncogene functions as a transcriptional co-activator of the Wnt/β-catenin pathway, which plays critical roles in CRC pathogenesis. Here we have identified a β-catenin-independent function of BCL9 in a poor-prognosis subtype of CRC tumors characterized by expression of stromal and neural associated genes. In response to spontaneous calcium transients or cellular stress, BCL9 is recruited adjacent to the interchromosomal regions, where it stabilizes the mRNA of calcium signaling and neural associated genes by interacting with paraspeckle proteins. BCL9 subsequently promotes tumor progression and remodeling of the tumor microenvironment (TME) by sustaining the calcium transients and neurotransmitter-dependent communication among CRC cells. These data provide additional insights into the role of BCL9 in tumor pathogenesis and point towards additional avenues for therapeutic intervention.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed cancer, which despite recent advances in treatment, remains incurable due to molecular heterogeneity of tumor cells
By interacting with paraspeckle proteins, which are involved in post transcriptional regulation, B-cell lymphoma 9 (BCL9) stabilizes the mRNA of calcium signaling and neural associated genes to confer neuronlike, multicellular communication properties to a poor prognosis molecular subtype of CRC
gene set enrichment analysis (GSEA) revealed that genes in the Black and Brown groups were involved in processes such as extracellular matrix remodeling, neuron differentiation, and wound healing (Fig. 2d). This result was validated in a different tissue microarray (TMA) (n = 84) from the one used in Fig. 1d–g, which showed high levels of BCL9 and RGS4 protein expression in FAP high compared with FAP low groups (Supplementary Fig. 7c); RGS4 displayed a positive correlation with BCL9 expression (Supplementary Fig. 7d, e). These results suggest that BCL9 downstream genes form a coregulation network that negatively correlates with prognosis, which provide a likely explanation as to why BCL9 expression predicts a poor prognosis in C1 only

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer, which despite recent advances in treatment, remains incurable due to molecular heterogeneity of tumor cells. For instance: (i) lens development is unaffected in mice with targeted deletion of the BCL9-HD2 domain[19]; (ii) BCL9 acts independently of β-catenin transcription during dental enamel formation[3]; (iii) BCL9 binds to proteins that transmit signals from estrogen and androgen receptors[20]; and (iv) the BCL9/MEF2D fusion protein found in patients with poor-prognosis B-ALL lacks the BCL9-HD2 domain[21,22]. These findings indicate that BCL9 is potentially a multifunctional protein and may have other unrelated roles Wnt/β-catenin co-activation. By interacting with paraspeckle proteins, which are involved in post transcriptional regulation, BCL9 stabilizes the mRNA of calcium signaling and neural associated genes to confer neuronlike, multicellular communication properties to a poor prognosis molecular subtype of CRC

Methods

Results

Conclusion