TRIM37 controls cancer-specific vulnerability to PLK4 inhibition

Abstract

Centrosomes catalyze microtubule formation for mitotic spindle assembly 1 . Centrosomes duplicate once per cell cycle in a process controlled the kinase PLK4 2 , 3 . Following chemical PLK4 inhibition, cell division in the absence of centrosome duplication generates centrosome-less cells that exhibit delayed, acentrosomal spindle assembly 4 . Whether PLK4 inhibitors can be leveraged for cancer treatment is not yet clear. Here, we show that acentrosomal spindle assembly following PLK4 inhibition depends on levels of the centrosomal ubiquitin ligase TRIM37. Low TRIM37 accelerates acentrosomal spindle assembly and improves proliferation following PLK4 inhibition, whereas high TRIM37 inhibits acentrosomal spindle assembly, leading to mitotic failure and cessation of proliferation. The Chr17q region containing the TRIM37 gene is frequently amplified in neuroblastoma and in breast cancer 5 – 8 , which renders these cancer types highly sensitive to PLK4 inhibition. TRIM37 inactivation improves acentrosomal mitosis because TRIM37 prevents PLK4 self-assembly into centrosome-independent condensates that serve as ectopic microtubule-organizing centers. By contrast, elevated TRIM37 expression inhibits acentrosomal spindle assembly via a distinct mechanism that involves degradation of the centrosomal component CEP192. Thus, TRIM37 is a critical determinant of mitotic vulnerability to PLK4 inhibition. Linkage of TRIM37 to prevalent cancer-associated genomic changes, including 17q gain in neuroblastoma and 17q23 amplification in breast cancer, may offer an opportunity to use PLK4 inhibition to trigger selective mitotic failure and provide new avenues to treatments for these cancers.

TRIM37 prevents formation of centriolar protein assemblies by regulating Centrobin

“…Moreover, while most centriolar proteins tested did not localize to Centrobin assemblies ( Figure 4—figure supplement 1A and C–E ), we found that SPICE did, although it was not needed for the formation of Centrobin assemblies ( Figure 4—figure supplement 1F,G ). Furthermore, we uncovered that PLK4 is also detected in Centrobin assemblies, which therefore likely coincide with the large PLK4 condensates that form in TRIM37-knock out RPE-1 cells (TRIM37-ko) ( Meitinger et al, 2020 ; Meitinger et al, 2016 ; Figure 4—figure supplement 1H ; Materials and methods). Just like for SPICE, we found that Centrobin assemblies generated upon TRIM37 depletion formed even when PLK4 was targeted using siRNAs ( Figure 4D,E ), despite the presence of monopolar mitotic figures attesting to the efficiency of depletion.…”

“…Furthermore, TRIM37 overexpression has been linked to increased cell invasion and metastasis in colorectal and hepatocellular carcinoma ( Hu and Gan, 2017 ; Jiang et al, 2015 ). Cancer cells overexpressing TRIM37 are hypersensitive to the absence of centrioles upon treatment with the PLK4 inhibitor Centrinone, because excess TRIM37 interferes with acentriolar spindle assembly, inducing mitotic failure ( Meitinger et al, 2020 ; Yeow et al, 2020 ). Moreover, such cells assemble small condensates harboring the centrosomal proteins CEP192 and CEP152, as well as inactive PLK4 ( Meitinger et al, 2020 ; Meitinger et al, 2016 ).…”

“…Cancer cells overexpressing TRIM37 are hypersensitive to the absence of centrioles upon treatment with the PLK4 inhibitor Centrinone, because excess TRIM37 interferes with acentriolar spindle assembly, inducing mitotic failure ( Meitinger et al, 2020 ; Yeow et al, 2020 ). Moreover, such cells assemble small condensates harboring the centrosomal proteins CEP192 and CEP152, as well as inactive PLK4 ( Meitinger et al, 2020 ; Meitinger et al, 2016 ). Interestingly, in addition, the absence of TRIM37 triggers the formation of larger condensates containing PLK4 ( Meitinger et al, 2020 ; Meitinger et al, 2016 ).…”

“…Moreover, such cells assemble small condensates harboring the centrosomal proteins CEP192 and CEP152, as well as inactive PLK4 ( Meitinger et al, 2020 ; Meitinger et al, 2016 ). Interestingly, in addition, the absence of TRIM37 triggers the formation of larger condensates containing PLK4 ( Meitinger et al, 2020 ; Meitinger et al, 2016 ). Overall, both depletion and excess of TRIM37 is accompanied by detrimental cellular consequences.…”

Identification of a Ubiquitination-Related Gene Risk Model for Predicting Survival in Patients With Pancreatic Cancer

“…Of the eight genes identified, seven genes (RNF7, NCCRP1, BRCA1, TRIM37, RNF25, CDC27, and UBE2H) have been reported to play roles in ubiquitination ( Asamitsu et al, 2003 ; Kallio et al, 2011 ; Link et al, 2016 ; Cho et al, 2018 ; Lim and Joo, 2020 ; Meitinger et al, 2020 ; Zhang et al, 2020 ). It has not been reported that NPEPPS directly participates in the process of ubiquitination, but NPEPPS is also known to degrade the tau protein, which accumulates and polymerizes in some neurodegenerative diseases ( Kudo et al, 2011 ).…”