Skp2 deficiency restricts the progression and stem cell features of castration-resistant prostate cancer by destabilizing Twist

Abstract

Castration-resistant prostate cancer (CRPC) remains a major clinical challenge due to the lack of effective targeted therapy for its treatment. The mechanism underlying how CRPC gains resistance towards hormone depletion and other forms of chemotherapy is poorly understood. Research on understanding the factors that drive these processes is desperately needed to generate new therapies to cure the disease. Here, we discovered a fundamental role of S-phase protein kinase 2 (Skp2) in the formation and progression of CRPC. In transgenic adenocarcinoma mouse prostate model, Skp2 depletion leads to a profound repression of prostate tumor growth and distal metastasis and substantially prolonged overall survival. We revealed that Skp2 regulates CRPC through Twist-mediated oncogenic functions including epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) acquisitions. Mechanistically, Skp2 interacted with Twist and promoted the non-degradative ubiquitination of Twist. Consequently, Skp2 stabilized Twist protein expression by preventing proteasomal degradation of Twist by β-TrCP. We found that Twist overexpression augments CSC self-renewal and population and that Skp2 inhibition reverts Twist’s effects on CSC regulation. Furthermore, genetically depleting or pharmacologically inactivating Skp2 synergistically re-sensitized CRPC cells towards chemotherapies such as paclitaxel or doxorubicin. Together, the current study uncovering Skp2-mediated Twist stabilization and oncogenic functions in CRPC offers new knowledge on how CRPC progresses and acquires chemoresistance during tumor progression. It provides prove-of principle that Skp2 targeting is a promising approach to combat metastatic CRPC by targeting Twist and CSCs.

Identification of key biomarkers and functional pathways in osteosarcomas with lung metastasis: Evidence from bioinformatics analysis

“…On the other hand, Skp2 could combine with Myc, Miz1 and p300 to form a transcriptional complex mediating the transcription of RhoA to participate in the invasion and metastasis of tumors [36] . Furthermore, SKP2 has also been proven to enhance tumor invasion ability by promoting epithelial-mesenchymal transition (EMT) process and matrix metalloproteinase (MMP) expression [37,38] . Based on these encouraging results, Zhang et al found knockdown of Skp2 could result in RhoA and MMP-9 inhibition, thereby signi cantly reducing tumor cell invasion and lung metastasis in an orthotopic mouse model of osteosarcoma [39] .…”

ROCK2 Confers Acquired Gemcitabine Resistance in Pancreatic Cancer Cells by Upregulating Transcription Factor ZEB1

“…We hypothesized that the doses of gemcitabine are too low to kill all GR cells, or that a small number of cells probably survive by regulating other resistance pathways (Supplementary Figure S15). However, not all the EMT-related chemoresistance is mediated by ZEB1, as reported that paclitaxel resistance in many cancer cells are conferred by overexpression of Twist [38,39]. It seems that chemoresistance in different cancer cells or induced by different chemotherapeutic drugs may depend on different mesenchymal proteins.…”

MiR‐339 depresses cell proliferation via directly targeting S‐phase kinase‐associated protein 2 mRNA in lung cancer

“…Highly expressed Skp2 can serve as a poor prognosis marker in non‐small cell lung cancer . The progression of castration‐resistant prostate cancer is modulated by Skp2 via destabilizing Twist . Lung cancer cells become sensitive to drugs for Skp2 inhibition .…”

“…Overexpressed Skp2 is able to depress the radiation‐induced bystander effects in esophageal carcinoma . Skp2 destabilizes Twist to regulate castration‐resistant prostate cancer progression . Skp2 is stabilized by mammalian target of rapamycin complex 1 (mTORC1)‐mediated phosphorylation in augmentation of gastric cancer .…”