CDK12 loss inhibits cell proliferation by regulating TBK1 in non-small cell lung cancer cells

Liu, Xiaoli; Liu, Yangdong; Chai, Wen-Jun; Yan, Mingxia; Li, Xiao Hui; Li, Jing; Sun, Lei; Cao, Yue; Liu, Qian; Sun, Yuexi; Pan, Hongyu

doi:10.1016/j.mcp.2023.101923

Cited by 1 publication

(4 citation statements)

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“…We identified that CDK12 is more expressed in LUAD and LUSC tumor tissue relative to normal tissue, and this is in alignment with a recent study by Liu et al [60]. Interestingly, CDK12 mutations in NSCLC samples did not impact the expression of a small subset of examined DDR and HR pathway genes [60]. Moreover, the siRNA-mediated depletion of CDK12 expression in the NSCLC cell lines A549 and H1299, harboring KRAS and NRAS mutations, respectively, conferred the inhibition of cell growth, as well as the growth using in vivo models, by inducing apoptosis [60].…”

Section: Discussionsupporting

confidence: 92%

“…The contribution of CDK12 to NSCLC tumorigenesis is relatively undescribed, but genomic alterations in the CDK12 gene occur in approximately 5% of the tumors [50]. We identified that CDK12 is more expressed in LUAD and LUSC tumor tissue relative to normal tissue, and this is in alignment with a recent study by Liu et al [60]. Interestingly, CDK12 mutations in NSCLC samples did not impact the expression of a small subset of examined DDR and HR pathway genes [60].…”

Section: Discussionsupporting

confidence: 89%

“…Interestingly, CDK12 mutations in NSCLC samples did not impact the expression of a small subset of examined DDR and HR pathway genes [60]. Moreover, the siRNA-mediated depletion of CDK12 expression in the NSCLC cell lines A549 and H1299, harboring KRAS and NRAS mutations, respectively, conferred the inhibition of cell growth, as well as the growth using in vivo models, by inducing apoptosis [60]. The effect of CDK12 depletion was proposed to be mediated by the downregulation of the expression of TBK1, which is encoded from a relatively long gene (100 kb).…”

Section: Discussionmentioning

confidence: 91%

“…The effect of CDK12 depletion was proposed to be mediated by the downregulation of the expression of TBK1, which is encoded from a relatively long gene (100 kb). The study by Liu et al indicates that CDK12 is a potential novel treatment target of NSCLC [60]. This notion is particularly important given that the function of CDK12 can be inhibited by small-molecule inhibitors that have already been explored related to, e.g., breast, ovarian, and prostate cancer therapy [50,61,62].…”

Section: Discussionmentioning

confidence: 99%

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Trans-Regulation of Alternative PD-L1 mRNA Processing by CDK12 in Non-Small-Cell Lung Cancer Cells

Larsen,

Maansson,

Daugaard

et al. 2023

Cells

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Immunotherapy using checkpoint inhibitors targeting the interaction between PD-1 on T cells and PD-L1 on cancer cells has shown significant results in non-small-cell lung cancer (NSCLC). Not all patients respond to the therapy, and PD-L1 expression heterogeneity is proposed to be one determinant for this. The alternative processing of PD-L1 RNA, which depends on an alternative poly-A site in intron 4, generates a shorter mRNA variant (PD-L1v4) encoding soluble PD-L1 (sPD-L1), relative to the canonical PD-L1v1 mRNA encoding membrane-associated PD-L1 (mPD-L1). This study aimed to identify factors influencing the ratio between these two PD-L1 mRNAs in NSCLC cells. First, we verified the existence of the alternative PD-L1 RNA processing in NSCLC cells, and from in silico analyses, we identified a candidate list of regulatory factors. Examining selected candidates showed that CRISPR/Cas9-generated loss-of-function mutations in CDK12 increased the PD-L1v4/PD-L1v1 mRNA ratio and, accordingly, the sPD-L1/mPD-L1 balance. The CDK12/13 inhibitor THZ531 could also increase the PD-L1v4/PD-L1v1 mRNA ratio and impact the PD-L1 transcriptional response to IFN-γ stimulation. The fact that CDK12 regulates PD-L1 transcript variant formation in NSCLC cells is consistent with CDK12’s role in promoting transcriptional elongation over intron-located poly-A sites. This study lays the groundwork for clinical investigations to delineate the implications of the CDK12-mediated balancing of sPD-L1 relative to mPD-L1 for immunotherapeutic responses in NSCLC.

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Section: Discussionsupporting

confidence: 92%