Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer.
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ABSTRACT:
SUBMITTER: Gong P
PROVIDER: S-EPMC6580093 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundTelomeres play an important role in colorectal cancer prognosis. Variation in telomere maintenance genes may be associated with survival after colorectal cancer diagnosis, but evidence is limited. In addition, possible interactions between telomere maintenance genes and prognostic factors, such as smoking and sex, also remain to be investigated.MethodsWe conducted gene-wide analyses of colorectal cancer prognosis in 4,896 invasive colorectal cancer cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); 1,871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and colorectal cancer-specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex. P values were adjusted using Bonferroni correction.ResultsThe association between minor allele of rs7200950 (ACD) with colorectal cancer-specific survival varied significantly by smoking pack-years (corrected P = 0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (TERF1), rs75676021 (POT1), and rs74429678 (POT1) were associated with decreased overall and/or colorectal cancer-specific survival in women but not in men.ConclusionsOur study reported a gene-wide statistically significant interaction with sex (TERF1, POT1). Although significant interaction by smoking pack-years (ACD) was observed, there was no evidence of a dose response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted.ImpactOur study found a gene-smoking and gene-sex interaction on survival after colorectal cancer diagnosis, providing new insights into the role of genetic polymorphisms in telomere maintenance on colorectal cancer prognosis.
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Project description:Recently, miR-124 has been regarded as a critical modulator of colorectal cancer. We here summarize the studies on the role and mechanism of miR-124 in colorectal cancer. They indicate that miR-124 is methylated during carcinogenesis and functions as a tumor-suppressor in colorectal cancer. miR-124 might serve as a potential diagnostic biomarker and therapeutic target in colorectal cancer in the foreseeable future.
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Project description:Translocase of outer mitochondrial membrane 20 (TOMM20) plays an essential role as a receptor for proteins targeted to mitochondria. TOMM20 was shown to be overexpressed in various cancers. However, the oncological function and therapeutic potential for TOMM20 in cancer remains largely unexplored. The purpose of this study was to elucidate the underlying molecular mechanism of TOMM20's contribution to tumorigenesis and to explore the possibility of its therapeutic potential using colorectal cancer as a model. The results show that TOMM20 overexpression resulted in an increase in cell proliferation, migration, and invasion of colorectal cancer (CRC) cells, while siRNA-mediated inhibition of TOMM20 resulted in significant decreases in cell proliferation, migration, and invasion. TOMM20 expression directly impacted the mitochondrial function including ATP production and maintenance of membrane potential, which contributed to tumorigenic cellular activities including regulation of S phase cell cycle and apoptosis. TOMM20 was overexpressed in CRC compared to the normal tissues and increased expression of TOMM20 to be associated with malignant characteristics including a higher number of lymph nodes and perineural invasion in CRC. Notably, knockdown of TOMM20 in the xenograft mouse model resulted in a significant reduction of tumor growth. This is the first report demonstrating a relationship between TOMM20 and tumorigenesis in colorectal cancer and providing promising evidence for the potential for TOMM20 to serve as a new therapeutic target of colorectal cancer. [BMB Reports 2019; 52(12): 712-717].
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Project description:Background:Serine/arginine protein kinase 1 (SRPK1) is a protein kinase that belongs to the serine/arginine-rich domain family of splicing factors which are essential for splice-site selection, especially the modulation for RNA metabolism, localization, and translation. High expression of SRPK1 has been found in numerous human cancers, but its mechanism in colorectal cancer (CRC) is still rarely reported. Purpose:To investigate the expression of SRPK1 in CRC tissues and cells and determine its functions and mechanism in CRC. Methods:The expression of SRPK1 was explored in human CRC patients and cells by immunohistochemistry, real-time quantitative PCR, and Western blot; Cell Counting Kit-8, Transwell, flow cytometry, and tube formation assay were used to investigate the CRC cell viability, migration, apoptosis, and angiogenesis, respectively. Results:SRPK1 was overexpressed in CRC tumor tissues and cells, and correlated with tumor node metastasis stage; inhibition of SRPK1 by siRNA resulted in decreased cell growth and migration, significantly increased apoptosis, and suppressed angiogenesis. Conclusion:SRPK1 can be a prognostic indicator of CRC and may be a therapeutic target for CRC.
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Project description:A variety of human tumors employ alternative and recombination-mediated lengthening for telomere maintenance (ALT). Human RecQ helicases, such as BLM and WRN, can efficiently unwind alternate/secondary structures during telomere replication and/or recombination. Here, we report a novel role for RECQL1, the most abundant human RecQ helicase but functionally least studied, in telomere maintenance. RECQL1 associates with telomeres in ALT cells and actively resolves telomeric D-loops and Holliday junction substrates. RECQL1 physically and functionally interacts with telomere repeat-binding factor 2 that in turn regulates its helicase activity on telomeric substrates. The telomeric single-stranded binding protein, protection of telomeres 1 efficiently stimulates RECQL1 on telomeric substrates containing thymine glycol, a replicative blocking lesion. Loss of RECQL1 results in dysfunctional telomeres, telomere loss and telomere shortening, elevation of telomere sister-chromatid exchanges and increased aphidicolin-induced telomere fragility, indicating a role for RECQL1 in telomere maintenance. Further, our results indicate that RECQL1 may participate in the same pathway as WRN, probably in telomere replication.
| S-EPMC4027191 | biostudies-literature
Project description:Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification.
| S-EPMC4999521 | biostudies-literature
Project description:BackgroundColorectal cancer is one of the most common causes of cancer death worldwide. Using cDNA microarray containing 23 040 genes, we earlier investigated gene-expression profiles in 11 colorectal cancers for the purpose of better understanding of colorectal carcinogenesis as well as development of novel diagnostic and therapeutic strategies. MRG-binding protein (MRGBP) or C20orf20, encoding a subunit of TRRAP/TIP60-containing histone acetyltransferase complex, was up-regulated in the majority of colorectal tumours.Methods and resultsThe elevated expression of MRGBP was observed in colorectal cancer tissues by quantitative PCR as well as immunohistochemical analyses. MRGBP marginally expressed in normal vital organs. Notably, suppressed MRGBP expression by MRGBP short hairpin RNA inhibited proliferation of colorectal cancer cells. Yeast two-hybrid screening and subsequent immunoprecipitation analysis identified bromodomain containing 8 (BRD8) as an MRGBP-interacting protein. As RNA interference against BRD8 also suppressed proliferation of colorectal cancer cells, BRD8 may be an important down-stream target of MRGBP.ConclusionThese results suggest that MRGBP has an important function in proliferation of cancer cells through the regulation of BRD8 and that MRGBP should be a novel therapeutic target for colorectal cancer.
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Project description:In advanced prostate cancer, resistance to androgen deprivation therapy is achieved through numerous mechanisms, including loss of the androgen receptor (AR) allowing for AR-independent growth. Therapeutic options are limited for AR-independent castration-resistant prostate cancer (CRPC), and defining mechanisms critical for survival is of utmost importance for targeting this lethal disease. Our studies focus on identifying telomere maintenance mechanism (TMM) hallmarks adopted by CRPC to promote survival. TMMs are responsible for telomere elongation to instill replicative immortality and prevent senescence, with the two TMM pathways available being telomerase and alternative lengthening of telomeres (ALT). Here, we show that AR-independent CRPC demonstrates an atypical ALT-like phenotype with variable telomerase expression and activity, whereas AR-dependent models lack discernible ALT hallmarks. In addition, AR-independent CRPC cells exhibited elevated levels of SLX4IP, a protein implicated in promoting ALT. SLX4IP overexpression in AR-dependent C4-2B cells promoted an ALT-like phenotype and telomere maintenance. SLX4IP knockdown in AR-independent DU145 and PC-3 cells led to ALT-like hallmark reduction, telomere shortening, and induction of senescence. In PC-3 xenografts, this effect translated to reduced tumor volume. Using an in vitro model of AR-independent progression, loss of AR in AR-dependent C4-2B cells promoted an atypical ALT-like phenotype in an SLX4IP-dependent manner. Insufficient SLX4IP expression diminished ALT-like hallmarks and resulted in accelerated telomere loss and senescence. IMPLICATIONS: This study demonstrates a unique reliance of AR-independent CRPC on SLX4IP-mediated ALT-like hallmarks and loss of these hallmarks induces telomere shortening and senescence, thereby impairing replicative immortality.
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Project description:MicroRNAs (miRs) are small noncoding RNAs that negatively regulate gene expression by binding to the three untranslated regions of their target mRNAs. Deregulations of miRs were shown to play pivotal roles in tumorigenesis and progression. Recent research efforts have been devoted to translating these basic discoveries into applications that could improve the therapeutic outcome of patients with cancer. MiR-34a is a highly conserved miR throughout many different species. In humans, there are three homologs (hsa-miR34a, hsa-miR-34b and hsa-miR-34c). Early studies have shown that miR-34a acts as a tumor-suppressor gene by targeting many oncogenes related to proliferation, apoptosis and invasion. In this review, we provide a complex overview of miR-34a, including regulating its expression, its known functions in cancer and future challenges as a potential therapeutic target in human cancers.
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Project description:Deubiquitination is a major form of post-translational protein modification involved in the regulation of protein homeostasis and various cellular processes. Deubiquitinating enzymes (DUBs), comprising about five subfamily members, are key players in deubiquitination. USP10 is a USP-family DUB featuring the classic USP domain, which performs deubiquitination. Emerging evidence has demonstrated that USP10 is a double-edged sword in human cancers. However, the precise molecular mechanisms underlying its different effects in tumorigenesis remain elusive. A possible reason is dependence on the cell context. In this review, we summarize the downstream substrates and upstream regulators of USP10 as well as its dual role as an oncogene and tumor suppressor in various human cancers. Furthermore, we summarize multiple pharmacological USP10 inhibitors, including small-molecule inhibitors, such as spautin-1, and traditional Chinese medicines. Taken together, the development of specific and efficient USP10 inhibitors based on USP10's oncogenic role and for different cancer types could be a promising therapeutic strategy.
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