MYBL2 disrupts the Hippo-YAP pathway and confers castration resistance and metastatic potential in prostate cancer

Abstract

Rationale: Resistance to androgen-deprivation therapy (ADT) associated with metastatic progression remains a challenging clinical task in prostate cancer (PCa) treatment. Current targeted therapies for castration-resistant prostate cancer (CRPC) are not durable. The exact molecular mechanisms mediating resistance to castration therapy that lead to CRPC progression remain obscure. Methods: The expression of MYB proto-oncogene like 2 (MYBL2) was evaluated in PCa samples. The effect of MYBL2 on the response to ADT was determined by in vitro and in vivo experiments. The survival of patients with PCa was analyzed using clinical specimens (n = 132) and data from The Cancer Genome Atlas (n = 450). The mechanistic model of MYBL2 in regulating gene expression was further detected by subcellular fractionation, western blotting, quantitative real-time PCR, chromatin immunoprecipitation, and luciferase reporter assays. Results: MYBL2 expression was significantly upregulated in CRPC tissues and cell lines. Overexpression of MYBL2 could facilitate castration-resistant growth and metastatic capacity in androgen-dependent PCa cells by promoting YAP1 transcriptional activity via modulating the activity of the Rho GTPases RhoA and LATS1 kinase. Importantly, targeting MYBL2, or treatment with either the YAP/TAZ inhibitor Verteporfin or the RhoA inhibitor Simvastatin, reversed the resistance to ADT and blocked bone metastasis in CRPC cells. Finally, high MYBL2 levels were positively associated with TNM stage, total PSA level, and Gleason score and predicted a higher risk of metastatic relapse and poor prognosis in patients with PCa. Conclusions: Our results reveal a novel molecular mechanism conferring resistance to ADT and provide a strong rationale for potential therapeutic strategies against CRPC.

MYBL2 Gene Polymorphism Is Associated With Acute Lymphoblastic Leukemia Susceptibility in Children

“…The expression of MYBL2 gene is controlled by other transcription factors or noncoding RNA (41)(42)(43)(44)(45), and the MYBL2 protein is activated via phosphorylation (14,21). After activated, MYBL2 regulates downstream diverse genes or proteins involved in multiple cellular processes, such as BCL2 and MYC in cell survival (46)(47)(48), cyclins and FGF4 in cell cycle (49-51), SOX2 and OCT4 in cell differentiation (52,53), SNAIL and YAP1 in cell invasion and metastasis (19,54). Overexpression or amplification of MYBL2 had been widely reported in previous studies on cancer.…”

“…Overexpression or amplification of MYBL2 had been widely reported in previous studies on cancer. For instance, MYBL2 was overexpressed in castration-resistant prostate cancer and promoted cell growth and metastatic by promoting YAP1 transcriptional activity (19). Liang et al reported that MYBL2 expression was increased in gallbladder cancer and could serve as a potential prognostic biomarker (55).…”

“…MYBL2 has also been demonstrated to act as an oncogene in numerous studies (14,15). MYBL2 promotes the malignant development of cancer via regulating various cellular processes including apoptosis, proliferation, differentiation, invasion, metastasis, and replication stress (12,(16)(17)(18)(19)(20). The aberrant expression or dysfunction of MYBL2 has been validated in a variety of cancers including adult leukemia, breast cancer, prostate cancer, ovarian cancer, liver cancer, and lung cancer (19)(20)(21)(22)(23)(24)(25).…”

A comprehensive investigation of m6A regulators prognostic value and associated molecular pathways in breast invasive cancer

“…MYBL2, another significantly upregulated gene in the altered group, is a member of MYB transcription family and a positive regulator of the cell cycle which binds to the promoter of G2/M phase genes, such as CCNB1, CDK1, CCNA2, BCL2, and BIRC5 [89,90]. Over-expression of MYBL2 is defined in several cancers such as breast [91] lung [92], esophagus [93], colorectal [94], bladder [95] and prostate [96] cancers. BIRC5 is a well-characterized anti-apoptotic gene playing a role in the presentation of apoptosis, and our results described it as one of the top upregulated genes in the altered group compared to the unaltered samples.…”

Deletion of Wild-type p53 Facilitates Bone Metastatic Function by Blocking the AIP4 Mediated Ligand-Induced Degradation of CXCR4

“…Western blotting was performed as described previously (Li et al, 2021). The following primary antibodies were used in this study: anti-p53 wild-type (clone PAb1620 (Puca et al, 2008); Merck Millipore, Billerica, MA, USA), anti-CXCR4 (ab124824; Abcam, Cambridge, United Kingdom), anti-AIP4 (NBP2-55083; Novus Biologicals, Littleton, CO, USA), anti-α-tubulin (T9026; Sigma-Aldrich), and anti-GAPDH (#97166; Cell Signaling Technology, Danvers, MA, USA) antibodies.…”