Keratin 19 (K19) belongs to the keratin family of proteins, which maintains structural integrity of epithelia. In cancer, K19 is highly expressed in several types where it serves as a diagnostic marker. Despite the positive correlation between higher expression of K19 in tumor and worse patient survival, the role of K19 in breast cancer remains unclear. Therefore, we ablated K19 expression in MCF7 breast cancer cells and found that K19 was required for cell proliferation. Transcriptome analyses of KRT19 knockout cells identified defects in cell cycle progression and levels of target genes of E2F1, a key transcriptional factor for the transition into S phase. Furthermore, proper levels of cyclin dependent kinases (CDKs) and cyclins, including D-type cyclins critical for E2F1 activation, were dependent on K19 expression, and K19-cyclin D co-expression was observed in human breast cancer tissues. Importantly, K19 interacts with cyclin D3, and a loss of K19 resulted in decreased protein stability of cyclin D3 and sensitivity of cells towards CDK inhibitor-induced cell death. Overall, these findings reveal a novel function of K19 in the regulation of cell cycle program and suggest that K19 may be used to predict the efficacy of CDK inhibitors for treatments of breast cancer.
PBRM1 is a subunit of the PBAF chromatin remodeling complex
that
uniquely contains six bromodomains. PBRM1 can operate as a tumor suppressor
or tumor promoter. PBRM1 is a tumor promoter in prostate cancer, contributing
to migratory and immunosuppressive phenotypes. Selective chemical
probes targeting PBRM1 bromodomains are desired to elucidate the association
between aberrant PBRM1 chromatin binding and cancer pathogenesis and
the contributions of PBRM1 to immunotherapy. Previous PBRM1 inhibitors
unselectively bind SMARCA2 and SMARCA4 bromodomains with nanomolar
potency. We used our protein-detected NMR screening pipeline to screen
1968 fragments against the second PBRM1 bromodomain, identifying 17
hits with K
d values from 45 μM to
>2 mM. Structure–activity relationship studies on the tightest-binding
hit resulted in nanomolar inhibitors with selectivity for PBRM1 over
SMARCA2 and SMARCA4. These chemical probes inhibit the association
of full-length PBRM1 to acetylated histone peptides and selectively
inhibit growth of a PBRM1-dependent prostate cancer cell line.
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