Haploinsufficiency for Microtubule Methylation Is an Early Driver of Genomic Instability in Renal Cell Carcinoma.

Chiang YC, Park IY, Terzo EA, Tripathi DN, Mason FM, Fahey CC, Karki M, Shuster CB, Sohn BH, Chowdhury P, Powell RT, Ohi R, Tsai YS, de Cubas AA, Khan A, Davis IJ, Strahl BD, Parker JS, Dere R, Walker CL, Rathmell WK
Cancer Res. 2018 78 (12): 3135-3146

PMID: 29724720 · PMCID: PMC6004258 · DOI:10.1158/0008-5472.CAN-17-3460

Loss of the short arm of chromosome 3 (3p) occurs early in >95% of clear cell renal cell carcinoma (ccRCC). Nearly ubiquitous 3p loss in ccRCC suggests haploinsufficiency for 3p tumor suppressors as early drivers of tumorigenesis. We previously reported methyltransferase , which trimethylates H3 histones on lysine 36 (H3K36me3) and is located in the 3p deletion, to also trimethylate microtubules on lysine 40 (αTubK40me3) during mitosis, with αTubK40me3 required for genomic stability. We now show that monoallelic, -deficient cells retaining H3K36me3, but not αTubK40me3, exhibit a dramatic increase in mitotic defects and micronuclei count, with increased viability compared with biallelic loss. In -inactivated human kidney cells, rescue with a pathogenic mutant deficient for microtubule (αTubK40me3), but not histone (H3K36me3) methylation, replicated this phenotype. Genomic instability (micronuclei) was also a hallmark of patient-derived cells from ccRCC. These data show that the tumor suppressor displays a haploinsufficiency phenotype disproportionately impacting microtubule methylation and serves as an early driver of genomic instability. Loss of a single allele of a chromatin modifier plays a role in promoting oncogenesis, underscoring the growing relevance of tumor suppressor haploinsufficiency in tumorigenesis. .

©2018 American Association for Cancer Research.

MeSH Terms (19)

Animals Carcinogenesis Carcinoma, Renal Cell Cell Line, Tumor Chromosomes, Human, Pair 3 Fibroblasts Gene Knockdown Techniques Genomic Instability Haploinsufficiency Histone-Lysine N-Methyltransferase Histones Humans Kidney Neoplasms Kidney Tubules, Proximal Lysine Methylation Mice Micronuclei, Chromosome-Defective Microtubules

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