CDK12: cellular functions and therapeutic potential of versatile player in cancer.
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ABSTRACT:
SUBMITTER: Pilarova K
PROVIDER: S-EPMC8210036 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cyclin-dependent kinases (CDKs) play critical roles in cell cycle progression and gene expression regulation. In human cancer, transcription-associated CDKs can activate oncogenic gene expression programs, whereas cell cycle-regulatory CDKs mainly induce uncontrolled proliferation. Cyclin-dependent kinase 12 (CDK12) belongs to the CDK family of serine/threonine kinases and has been recently found to have multiple roles in gene expression regulation and tumorigenesis. Originally, CDK12 was thought to be one of the transcription-associated CDKs, acting with its cyclin partner Cyclin K to promote the phosphorylation of the C-terminal domain (CTD) of RNA polymerase II and induce transcription elongation. However, recent studies have demonstrated that CDK12 also controls multiple gene expression processes, including transcription termination, mRNA splicing, and translation. Most importantly, CDK12 mutations are frequently found in human tumors. Loss of CDK12 function causes defective expression of DNA damage response (DDR) genes, which eventually results in genome instability, a hallmark of human cancer. Here, we discuss the diverse roles of CDK12 in gene expression regulation and human cancer, focusing on newly identified CDK12 kinase functions in cellular processes and highlighting CDK12 as a promising therapeutic target for human cancer treatment.
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Project description:Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases that regulate transcriptional and post-transcriptional processes, thereby modulating multiple cellular functions. Early studies characterised CDK12 as a transcriptional CDK that complexes with cyclin K to mediate gene transcription by phosphorylating RNA polymerase II. CDK12 has been demonstrated to specifically upregulate the expression of genes involved in response to DNA damage, stress and heat shock. More recent studies have implicated CDK12 in regulating mRNA splicing, 3' end processing, pre-replication complex assembly and genomic stability during embryonic development. Genomic alterations in CDK12 have been detected in oesophageal, stomach, breast, endometrial, uterine, ovarian, bladder, colorectal and pancreatic cancers, ranging from 5% to 15% of sequenced cases. An increasing number of studies point to CDK12 inhibition as an effective strategy to inhibit tumour growth, and synthetic lethal interactions have been described with MYC, EWS/FLI and PARP/CHK1 inhibition. Herein, we discuss the present literature on CDK12 in cell function and human cancer, highlighting important roles for CDK12 as a clinical biomarker for treatment response and potential as an effective therapeutic target.
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Project description:p97/VCP, a member of the AAA-ATPase super family, has been associated with a wide variety of essential cellular protein pathways com prising: (i) nuclear envelope reconstruction, (ii) cell cycle, (iii) Golgi reassembly, (iv) suppression of apoptosis and (v) DNA-damage response [1-6]. In addition, vasolin-containing protein (VCP) dislodges the ubiquitinated proteins from the endoplasmic reticulum (ER) and chaperones them to the cytosol for proteasomal degradation by endoplasmic reticulum-associated degradation (ERAD) [7]. The interactions of VCP in the endoplasmic reticulum-associated degradation (ERAD) pathway determine the substrate selection for proteasomal degradation. Moreover, the interaction with VCP is also required for the ubiquitination of substrate. VCP is phosphorylated by the master cellular kinase, Akt as a mechanism to regulate ERAD [8]. These multiple interactions in protein degradation pathways points to central role of VCP in misfolded protein degradation. VCP has a polyglutamine and ubiquitin-binding capacity and is involved in proteasomal degradation, cytosolic aggregation and processing of polyQ and polyUb aggregates in neurodegenerative and other misfolded protein diseases [9, 10]. Mutations in VCP gene are also linked to a protein deposition disorder, IBMFD [11]. We propose VCP as a therapeutic target for diseases caused by cytosolic protein aggregation or degradation of misfolded protein. We predict that selective interference of VCP interaction(s) with aberrant protein or its ERAD function will be an effective therapeutic site to rescue functional misfolded protein in diseases like cystic fibrosis and alpha-1-trypsin deficiency. The control of VCP expression is also proposed to be a potential therapeutic target in ex-polyQ-induced neurodegenerative diseases [12]. The further functional characterization of VCP and associated proteins in these diseases will help in designing of selective therapeutics.
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Project description:Liver cancer is a leading cause of cancer deaths worldwide. Hepatocellular carcinoma (~75-85%) and cholangiocarcinoma (~10-15%) account for the majority of primary liver malignancies. Patients with primary liver cancer are often diagnosed with unresectable diseases and do not respond well to current therapies. The liver is also a common site of metastasis. Liver metastasis is difficult to treat, and the prognosis is poor. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with immunosuppressive activity. MDSCs are an important component of the tumor microenvironment and promote tumor progression through various mechanisms. MDSCs expand in both liver cancer patients and mouse liver cancer models. Importantly, MDSCs correlate with poor clinical outcomes for liver cancer patients. The tumor-promoting functions of MDSCs have also been shown in mouse liver cancer models. All these studies suggest that targeting MDSCs can potentially benefit liver cancer treatment. This review summarizes the current findings of MDSC regulation in liver cancer and related disease conditions.
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Project description:Background: Gastric cancer remains the second leading cause of cancer-related death, and the third in mortality due to lack of effective therapeutic targets for late stage cancer patients. This study aims to identify potential druggable target biomarkers as potential therapeutic options for patients with gastric cancer. Methods: Immunohistochemistry of human gastric tumor tissues was conducted to determine the expression level of cyclin-dependent kinase 12 (CDK12). Multiple in vitro and in vivo assays such as RNAi, mass spectrometry, computer docking models, kinase assays, cell xenograft NU/NU mouse models (CDXs) and patient-derived xenograft NOD/SCID mouse models (PDXs) were conducted to study the function and molecular interaction of CDK12 with p21 activated kinase 2 (PAK2), as well as to find CDK12 inhibitors as potential treatment options for human gastric cancer. Results: Here we identified that CDK12 is a driver gene in human gastric cancer growth. Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway. We further identified FDA approved clinical drug procaterol can serve as an effective CDK12 inhibitor, leading to dramatic restriction of cancer cell proliferation and tumor growth in human gastric cancer cells and PDXs. Conclusions: Our data highlight the potential of CDK12/PAK2 as therapeutic targets for patients with gastric cancer, and we propose procaterol treatment as a novel therapeutic strategy for human gastric cancer.
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