Paired related homeobox 1 transactivates dopamine D2 receptor to maintain propagation and tumorigenicity of glioma-initiating cells

GUoblastoma multiforme （GBM） is a highly invasive brain tumor with limited therapeutic means and poor prognosis. Recent stud- ies indicate that glioma-initiating ceUs/gUoma stem ceils （GICs/GSCs） may be responsible for tumor initiation, infiltration, and recurrence. GICs could aberrantly employ molecular machinery balancing self-renewal and differentiation of embryonic neural precursors. Here, we find that paired related homeobox 1 （PRRX1）, a homeodomain transcription factor that was previously reported to control skeletal development, is expressed in cortical neural progenitors and is required for their self-renewal and proper differentiation. Further, PRRX1 is overrepresented in gUoma samples and labels GlCs. Gtioma celts and GlCs depleted with PRRX1 could not propagate in vitro or form tumors in the xenograft mouse model. The GIC self-renewal function regulated by PRRX1 is mediated by dopamine D2 receptor （DRD2）. PRRX1 directly binds to the DRD2 promoter and transactivates its expression in GICs. Blockage of the DRD2 signaling hampers GIC self-renewal, whereas its overexpression restores the propagating and tumorigenic potential of PRRXl-depleted GlCs. Finally, PRRX1 potentiates GICs via DRD2-mediated extracetlutar signal-related kinase （ERK） and AKT activation. Thus, our study suggests that therapeutic targeting the PRRX1-DRD2-ERK/AKT axis in GICs is a promising strategy for treating GBMs.

PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain

How PD-L1 expression is regulated in cancer is poorly understood.Here,we report that the ATP-binding activity of ERBB3 pseudokinase regulates PD-L1 gene expression in colorectal cancers(CRCs).ERBB3 is one of the four members of the EGF receptor family,all with protein tyrosine kinase domains.ERBB3 is a pseudokinase with a high binding affin-ity to ATP.We showed that ERBB3 ATP-binding inactivation mutant reduces tumorigenicity in genetically engineered mouse models and impairs xenograft tumor growth of CRC cell lines.The ERBB3 ATP-binding mutant cells dramatically reduce IFN-g-induced PD-L1 expres-sion.Mechanistically,ERBB3 regulates IFN-g-induced PD-L1 expression through the IRS1-PI3K-PDK1-RSK-CREB signaling axis.CREB is the transcription factor that regulates PD-L1 gene expression in CRC cells.Knockin of a tumor-derived ERBB3 mutation located in the ki-nase domain sensitizes mouse colon cancers to anti-PD1 antibody therapy,suggesting that ERBB3 mutations could be predictive biomarkers for tumors amenable to immune check-point therapy.

Long non-coding RNA LncKdm2b regulates cortical neuronal differentiation by cis-activating Kdm2b

The mechanisms underlying spatial and temporal control of cortical neurogenesis of the brain are largely elusive.Long non-coding RNAs(lncRNAs)have emerged as essential cell fate regulators.Here we found LncKdm2b(also known as Kancr),a lncRNA divergently transcribed from a bidirectional promoter of Kdm2b,is transiently expressed during early differentiation of cortical projection neurons.Interestingly,Kdm2b’s transcription is positively regulated in cis by LncKdm2b,which has intrinsic-activating function and facilitates a permissive chromatin environment at the Kdm2b’s promoter by associating with hnRNPAB.Lineage tracing experiments and phenotypic analyses indicated LncKdm2b and Kdm2b are crucial in proper differentiation and migration of cortical projection neurons.These observations unveiled a lncRNA-dependent machinery in regulating cortical neuronal differentiation.

Transcriptome Analysis Identifies SenZfp536,a Sense LncRNA that Suppresses Self-renewal of Cortical Neural Progenitors

Long non-coding RNAs(lncRNAs)regulate transcription to control development and homeostasis in a variety of tissues and organs.However,their roles in the development of the cerebral cortex have not been well elucidated.Here,a bioinformatics pipeline was applied to delineate the dynamic expression and potential cis-regulating effects of mouse lncRNAs using transcriptome data from 8 embryonic time points and sub-regions of the developing cerebral cortex.We further characterized a sense lncRNA,SenZfp536,which is transcribed downstream of and partially overlaps with the protein-coding gene Zfp536.Both SenZfp536 and Zfp536 were predominantly expressed in the proliferative zone of the developing cortex.Zfp536 was cis-regulated by SenZfp536,which facilitates looping between the promoter of Zfp536 and the genomic region that transcribes SenZfp536.Surprisingly,knocking down or activating the expression of SenZfp536 increased or compromised the proliferation of cortical neural progenitor cells(NPCs),respectively.Finally,overexpressing Zfp536 in cortical NPCs reversed the enhanced proliferation of cortical NPCs caused by SenZfp536 knockdown.The study deepens our understanding of how lncRNAs regulate the propagation of cortical NPCs through cis-regulatory mechanisms.