Retinoblastoma (RB) protein can exert tumor suppressor functions even when it becomes phosphorylated. It is thus essential to understand how phosphorylated RB (p-RB) expression and function are regulated. Here, we demonstrated that RING finger domain protein TRIM28 bound and promoted ubiquitination and degradation of CDK4/6-phosphorylated RB protein. SETDB1, a known TRIM28 binding partner, protected p-RB from degradation through the binding of methylated RB by its Tudor domain independent of its methyltransferase activity. SETDB1 was found to be frequently overexpressed due to gene amplification and positively correlated with p-RB in prostate cancer patient specimens. Inhibition of SETDB1 expression using a gene-specific antisense oligonucleotide (ASO) reduced tumor growth but accelerated RB protein degradation, limiting the therapeutic efficacy. However, coadministration of the CDK4/6 inhibitor palbociclib blocked ASO-induced RB degradation and resulted in a much greater cancer-inhibitory effect than each inhibitor alone both in vitro and in vivo. This study identified CDK4/6-dependent, TRIM28-mediated proteasomal degradation as a mechanism of RB inactivation and reveals SETDB1 as a key inhibitor of this process. Our findings suggest that combined targeting of SETDB1 and CDK4/6 represents a viable approach for the treatment of cancers with SETDB1 gene amplification or overexpression. Significance: The identification of a role for TRIM28 and SETDB1 in regulating CDK4/6-phosphorylated RB stability uncovers a combination strategy using CDK4/6 and SETDB1 inhibition to decrease RB degradation and inhibit cancer growth.

Background: Our study was designed to elucidate the morbidity trends of prostate cancer in low-incidence countries. Methods: Data on prostate cancer were extracted from the 2019 Global Burden of Disease study. A cluster analysis of growth rates stratified by age was conducted, and correlation analyses were performed between age-standardized incidence rates (ASIR), estimated annual percent change (EAPC), and socio-demographic index (SDI). Results: Among 35 low-incidence countries for prostate cancer, predominantly located in Asia and North Africa, the SDI ranged from low to high-middle levels. Higher SDI regions exhibited considerably higher ASIR. With the exception of Kyrgyzstan, Kiribati, and Samoa that experienced a decrease in ASIR, the remaining 32 countries displayed an upward morbidity trend since 1990, with all their EAPCs exceeding the global average. In addition, men ages 90 years and above consistently exhibited the highest ASIR for prostate cancer. The most notable growth rate of ASIR was observed in individuals ages 20 to 44 years. Conclusions: Overall, low-incidence countries generally witnessed an increase in prostate cancer morbidity, albeit at levels lower than those seen in Western countries. Individuals ages 90 years and above consistently maintained the highest ASIR since 1990. Notably, more substantial increase of ASIR in younger age was also observed in low-incidence countries. Impact: This study offers a comprehensive overview of prostate cancer morbidity in low-incidence countries worldwide from 1990 to 2019. Future research should delve into the associations between incidence, clinical stages, PSA screening, environmental factors, lifestyle, and genetic risk in these low-incidence countries.

Early detection of prostate cancer (PCa) is crucial for better patient outcomes. However, due to overdiagnosis with the current biopsy strategy, there is a need to improve and refine the biopsy strategy. The aim of this study was to thoroughly evaluate existing biopsy schemes for patients with suspicious lesions. This study conducted a systematic review and network meta-analysis following PRISMA guidelines (from their start until 15 January 2025), evaluating 13 biopsy schemes for detecting PCa in MRI-positive (PIRADS/Likert score 2-5) patients. Data from PubMed, Embase, and Cochrane databases were examined to assess the efficacy of biopsy schemes in detecting clinically significant (csPCa) and clinically insignificant (ciPCa) prostate cancer. This study is registered with PROSPERO (CRD42024551971). The analysis included 211 studies involving 74,113 individuals. When compared with the combination of systematic biopsy (SB, defined as <20 cores) and targeted biopsy (TB, defined as <6 cores) (SB+TB), ipsilateral SB with TB (ips-SB+TB) and saturation TB did not show statistically significant inferior detection rate of csPCa (ips-SB+TB: RR 0.95, 95% CrI 0.88, 1.02; saturation TB: RR 0.96, 95% CrI 0.91, 1.01). Meanwhile, there was no significant difference in csPCa detection rates for saturation SB+TB, SB+saturation TB compared to SB+TB (saturation SB+TB: RR 1.04, 95% CrI 0.98, 1.11; SB+saturation TB: RR 1.14, 95% CrI 0.999, 1.30). TB and SB alone detected significantly less csPCa than SB+TB (TB: RR 0.86, 95% CrI 0.84, 0.88; SB: RR 0.75, 95% CrI 0.73, 0.77). Saturation SB also did not show significant superiority in detecting csPCa. Additionally, saturation TB and ips-SB+TB also decrease the detection of ciPCa. (ips-SB+TB: RR 0.87, 95% CrI 0.72, 1.04; saturation TB: RR 0.76, 95% CrI 0.65, 0.88). The network meta-analysis reveals that saturation SB+TB and SB+saturation TB have no significant difference in csPCa detection between them and SB+TB. Meanwhile, ips-SB+TB and saturation TB are effective biopsy strategies for MRI-positive PCa patients, offering a more targeted approach for detecting csPCa. The National Natural Science Foundation of China (Grant number: 81500522) and Science & Technology Department of Sichuan Province (Grant number: 2020YFS0090, 2020YFS0046) and Cadre Health Research Project of Sichuan Province (Grant number: ZH2023-102).

Prostate cancer is the second most common cancer in men globally. Advances in diagnostic techniques, particularly multiparametric magnetic resonance imaging and the Prostate Imaging Reporting and Data System, have enhanced detection precision. However, optimal biopsy strategies for lesions with Prostate Imaging Reporting and Data System scores of 3-5 remain uncertain. Here we show that saturation targeted biopsy and ipsilateral systematic biopsy combined with targeted biopsy achieve comparable detection rates of clinically significant prostate cancer to the combined systematic and targeted biopsy approach for Prostate Imaging Reporting and Data System 3-5 lesions, while reducing unnecessary biopsies. Targeted biopsy alone remains insufficient, and omitting systematic biopsy in Prostate Imaging Reporting and Data System 5 lesions is not supported. These findings support tailored biopsy strategies based on Prostate Imaging Reporting and Data System scores, optimizing resource allocation and minimizing overdiagnosis. Further validation in larger cohorts with standardized protocols is necessary.

Retinoblastoma (RB) protein can exert tumor suppressor functions even when it becomes phosphorylated. It is thus essential to understand how phosphorylated RB (p-RB) expression and function are regulated. Here, we demonstrated that RING finger domain protein TRIM28 bound and promoted ubiquitination and degradation of CDK4/6-phosphorylated RB protein. SETDB1, a known TRIM28 binding partner, protected p-RB from degradation through the binding of methylated RB by its Tudor domain independent of its methyltransferase activity. SETDB1 was found to be frequently overexpressed due to gene amplification and positively correlated with p-RB in prostate cancer patient specimens. Inhibition of SETDB1 expression using a gene-specific antisense oligonucleotide (ASO) reduced tumor growth but accelerated RB protein degradation, limiting the therapeutic efficacy. However, coadministration of the CDK4/6 inhibitor palbociclib blocked ASO-induced RB degradation and resulted in a much greater cancer-inhibitory effect than each inhibitor alone both in vitro and in vivo. This study identified CDK4/6-dependent, TRIM28-mediated proteasomal degradation as a mechanism of RB inactivation and reveals SETDB1 as a key inhibitor of this process. Our findings suggest that combined targeting of SETDB1 and CDK4/6 represents a viable approach for the treatment of cancers with SETDB1 gene amplification or overexpression.Significance:The identification of a role for TRIM28 and SETDB1 in regulating CDK4/6-phosphorylated RB stability uncovers a combination strategy using CDK4/6 and SETDB1 inhibition to decrease RB degradation and inhibit cancer growth.