A CRISPR Interference of CBP and p300 Selectively Induced Synthetic Lethality in Bladder Cancer Cells In Vitro

Abstract

The transcriptional coactivator CREB-binding protein (CBP) and p300 are adenoviral E1A-binding proteins involved in various cellular processes, including embryonic development, homeostasis, cell differentiation and transcription activation. Previous study suggested that synthetic lethality between CBP and p300 inhibition in lung and hematopoietic cancers. However, the underlying mechanism of CBP and p300 paralog in bladder cancer remains unknown. In this study, we discovered that combined CBP and p300 inhibition impaired cell proliferation and induced apoptosis of bladder cancer cells and normal bladder urothelial cell via decreasing c-Myc expression. Then, we employed the dCas9-KRAB system, hTERT promoter and hUPII promoter to construct an CRISPR interference system which could specifically repress CBP and p300 expression and cause lethality in bladder cancer cells in vitro . The CRISPR interference system we constructed could specifically inhibit the progression of bladder cancer, providing a novel strategy to fight against bladder cancer.

LncARSR sponges miR-129-5p to promote proliferation and metastasis of bladder cancer cells through increasing SOX4 expression

“…Early diagnosis and treatment of this disease is closely related to the prognosis of patients 4. Recurrence and metastasis of Bca is the main reason for the failure of current therapy 5. However, precise molecular biological changes in Bca remain unclear.…”

Targeting Cancer with CRISPR/Cas9-Based Therapy

“…An alternative approach was used in a recent study conducted by Li et al In this experiment sgRNAs targeting genes inducing synthetic lethality (CBP and p300) were placed under control of cancer-specific promoter (hTERT) and bladder-specific promoter (hUPII), the same promoters used in the logical AND gate described earlier [ 71 ]. As a result, dCas9-KRAB inhibited the expression of both of those genes only in bladder cancer cells, inducing their apoptosis [ 91 ].…”

Targeting MYC to Combat Pancreatic Cancer

“…In summary, with the introduction of the concept of SL, researchers can postulate the synthetic lethal relationship of MYC with various molecules or events previously mentioned, such as CDK1/2, Aurora kinase, BTE inhibition, and p300 inactivation, which was validated by continuous preclinical advances in other malignancies. 83,120,[133][134][135][136] Despite the slow progress in the SLbased therapy of PADC, a bright prospect is well-expected, considering the strong connection between PADC and MYC overexpression. Further developments are required before these synthetic lethal targets can bring clinical benefits.…”