CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion.
CDK12 (cyclin-dependent kinase 12) is a regulatory kinase with evolutionarily conserved roles in modulating transcription elongation. Recent tumor genome studies of breast and ovarian cancers highlighted recurrent CDK12 mutations, which have been shown to disrupt DNA repair in cell-based assays. In breast cancers, CDK12 is also frequently co-amplified with the HER2 (ERBB2) oncogene. The mechanisms underlying functions of CDK12 in general and in cancer remain poorly defined. Based on global analysis of mRNA transcripts in normal and breast cancer cell lines with and without CDK12 amplification, we demonstrate that CDK12 primarily regulates alternative last exon (ALE) splicing, a specialized subtype of alternative mRNA splicing, that is both gene- and cell type-specific. These are unusual properties for spliceosome regulatory factors, which typically regulate multiple forms of alternative splicing in a global manner. In breast cancer cells, regulation by CDK12 modulates ALE splicing of the DNA damage response activator ATM and a DNAJB6 isoform that influences cell invasion and tumorigenesis in xenografts. We found that there is a direct correlation between CDK12 levels, DNAJB6 isoform levels and the migration capacity and invasiveness of breast tumor cells. This suggests that CDK12 gene amplification can contribute to the pathogenesis of the cancer.
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver V5Z 1L3, Canada.
Jerry F
JF
Tien
Graduate Bioinformatics Training Program, University of British Columbia, Vancouver V5Z 4S6, Canada.|Department of Molecular Oncology, BC Cancer Agency, Vancouver V5Z 1L3, Canada.
Alborz
A
Mazloomian
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver V5Z 1L3, Canada.
S-W Grace
SG
Cheng
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver V5Z 1L3, Canada.
Christopher S
CS
Hughes
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver V5Z 1L3, Canada.
Christalle C T
CCT
Chow
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver V5Z 1L3, Canada.
Leanna T
LT
Canapi
Department of Molecular Oncology, BC Cancer Agency, Vancouver V5Z 1L3, Canada.
Arusha
A
Oloumi
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver V5Z 1L3, Canada.
Genny
G
Trigo-Gonzalez
Department of Molecular Oncology, BC Cancer Agency, Vancouver V5Z 1L3, Canada.
Ali
A
Bashashati
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver V6T 2B5, Canada.
James
J
Xu
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver V5Z 1L3, Canada.
Vicky C-D
VC
Chang
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver V5Z 1L3, Canada.|Department of Molecular Oncology, BC Cancer Agency, Vancouver V5Z 1L3, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver V6T 2B5, Canada.
Sohrab P
SP
Shah
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver V5Z 1L3, Canada.|Department of Molecular Oncology, BC Cancer Agency, Vancouver V5Z 1L3, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver V6T 2B5, Canada.
Samuel
S
Aparicio
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver V5Z 1L3, Canada.|Department of Medical Genetics, University of British Columbia, Vancouver V6H 3N1, Canada.
Gregg B
GB
Morin
D017398:Alternative Splicing; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D004260:DNA Repair; D005091:Exons; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D026723:Polyadenylation; D060066:Protein Interaction Maps; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
C485565:DNAJB6 protein, human; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C447339:CDK12 protein, human; D018844:Cyclin-Dependent Kinases