Chen, B.-H. | Search bioRxiv

bioRxiv2018

Targeting BMI1 and MCL1 for Lung Adenocarcinoma Treatment

Lung cancer is the leading cause of cancer-associated death worldwide. Early metastasis and the recurrence remain major challenges for lung cancer treatment in clinic. Targeting the cancer stemness could be a potential strategy to restrain tumor progression. In the current study, we found that in lung adenocarcinoma (LAC), BMI1 and MCL1 play crucial roles in invasion, chemo-resistance, and tumor initiation. JNK signaling is a link between oncogenic pathway or environment stress to cancer stemness. The activation of JNK, either by EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3-ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small-molecule BI-44 was synthesized, which effectively suppressed BMI1/MCL1 expression and inhibited tumor formation and progression in preclinical models. Targeting BMI1/MCL1 provides the basis for a new therapeutic approach in the treatment of LAC.

cancer biology↗

bioRxiv2018

Pericarp Pigmentation in ‘Red Delicious’ and Its Four Generation Mutants Correlates with Hormones

Bud sport mutants of apple (Malus domestica Borkh.) trees with a highly blushed colouring pattern are mainly caused by the accumulation of anthocyanins in the pericarp. Hormones are important factors modulating anthocyanin accumulation. However, a good understanding of the interplay between hormones and anthocyanin synthesis in apples, especially in mutants at the molecular level, remains elusive. Here, physiological and comparative transcriptome approaches were used to reveal the molecular basis of pericarp pigmentation in Red Delicious and its mutants, including Starking Red, Starkrimson, Campbell Redchief and Vallee spur, which were designated G0 to G4, respectively. Pericarp pigmentation gradually proliferated from G0 to G4. The anthocyanin content was higher in the mutants than in Red Delicious. The activation of early phenylpropanoid biosynthesis genes, including ASP3, PAL, 4CL, PER, CHS, CYP98A and F3H, was responsible for anthocyanin accumulation in mutants. In addition, IAA and ABA had a positive regulatory effect on the synthesis of anthocyanins, while GA had the reverse effect. The down-regulation of AACT1, HMGS, HMGR, MVK, MVD2, IDI1 and FPPS2 involved in terpenoid biosynthesis influences anthocyanin accumulation by positively regulating transcripts of AUX1 and SAUR that contribute to the synthesis of IAA, GID2 to GA, PP2C and SnRK2 to ABA. Furthermore, MYB and bHLH members, which are highly correlated (r=0.882-0.980) with anthocyanin content, modulated anthocyanin accumulation by regulating the transcription of structural genes, including CHS and F3H, involved in the flavonoid biosynthesis pathway.

bioinformatics↗