The role of human cell division cycle 73 (CDC73) in human cancers has sparked controversy; however, its significance in oesophageal cancer remains elusive. This study aimed to elucidate CDC73 expression and its biological implications in human oesophageal cancer. Our findings unveiled a notable upregulation of CDC73 in both oesophageal cancer cell lines and tissues. Importantly, elevated CDC73 levels in patients with oesophageal cancer correlated with an unfavourable prognosis. Functional investigations revealed that CDC73 knockdown effectively curtailed the proliferation and growth of oesophageal cancer cells both in vitro and in vivo. Mechanistically, RRP15 emerged as a potential downstream target of CDC73 through a screening process involving identification of the top co-expressed genes, subsequent knockdown experiments, and observation of significant inhibition of cell proliferation, with RRP15 showing the most pronounced effect. This finding was further supported by the positive correlation observed between CDC73 and RRP15 in ESCA samples analysed using the ENCORI Pan-Cancer Analysis Platform. Notably, depletion of RRP15 in CDC73-overexpressing cells led to a shift from augmented to diminished tumour growth. Collectively, our findings underscore the pivotal role of CDC73 in oesophageal cancer through the modulation of RRP15 expression, suggesting CDC73 as a potential therapeutic target for treating oesophageal cancer.

A total of 1 out of 10 patients with primary hyperparathyroidism (PHP) presents an underlying genetic form, such as multiple endocrine neoplasia types 1, 2A, etc., as well as hyperparathyroidism-jaw tumour syndrome (HJT). We aimed to summarise the recent data, thus raising more awareness regarding HJT, from the clinical perspective of PHP in association with the challenges and pitfalls of CDC73 genetic testing and parafibromin staining. This narrative review included a sample-focused analysis from the past decade according to a PubMed search. We identified 17 original human studies (≥4 patients per article). The mean age at disease onset was between 20.8 and 39.5 years, while the largest study found that 71% of patients had HJT recognised before the age of 30. Males and females seemed to be equally affected, in contrast with sporadic PHP. PHP represented the central manifestation of HJT, occurring as the first manifestation in up to 85% of HJT cases. A biochemistry panel found a mean serum calcium level above the level of 12 mg/dL in PHP. PTH was elevated in HJT as well, with average values of at least 236.6 pg/mL. The most frequent pathological type in PHP was a parathyroid adenoma, but the incidence of a parathyroid carcinoma was much higher than in non-HJT cases (15% of all parathyroid tumours), with the diagnosis being established between the age of 15 and 37.5. In some families up to 85% of carriers suffered from a parathyroid carcinoma thus indicating that certain CDC73 pathogenic variants may harbour a higher risk. An important issue in HJT was represented by the parafibromin profile in the parathyroid tumours since in HJT both parathyroid adenomas and carcinomas might display a deficient immunoreactivity. Another frequent manifestation in HJT was ossifying fibromas of the jaw (affecting 5.4% to 50% of patients; the largest study found a prevalence of 15.4%). HJT was associated with a wide variety of kidney lesion (mostly: kidney cysts, with a prevalence of up to 75%, and renal tumours involved in 19% of patients). The risk of uterine lesions seemed increased in HJT, especially with concern to leiomyomas, adenofibromas, and adenomyosis. The underlying pathogenic mechanisms and the involvement of CDC73 pathogenic variants and parafibromin expression are yet to be explored. Currently, the heterogeneous expression of parafibromin status and, the wide spectrum of CDC73 mutations including the variety of clinical presentations in HJT, make it difficult to predict the phenotype based on the genotype. The central role of HJT-PHP is, however, the main clinical element, while the elevated risk of parathyroid carcinoma requires a special awareness.

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UBR5 is a HECT domain E3 ubiquitin ligase that is frequently amplified in breast, ovarian and prostate cancers. Heightened UBR5 expression plays a profound role in tumor growth through immune-dependent mechanisms; however, its mode of action in driving tumor metastasis has not been definitively delineated. Herein, we used a tetracycline (Tet)-inducible RNAi-mediated expression silencing cell system to investigate how UBR5 enables postsurgical mammary tumor metastatic growth in mouse lungs without the continuous influence of the primary lesion. In vitro, Ubr5 knockdown induces morphological and molecular changes characteristic of epithelial-mesenchymal transition (EMT). In vivo, UBR5 promotes lung metastasis in an E3 ubiquitin ligase-dependent manner. Moreover, doxycycline-induced UBR5 expression knockdown in metastatic cells in the lungs, following removing the primary tumors, resulted in increased apoptosis, decreased proliferation and prolonged survival, whereas silencing the expression of cell division cycle 73 (CDC73), a tumor suppressor and E3 ligase substrate of UBR5, reversed these effects. Transcriptome analyses revealed a prominent role of the p53 pathway in dovitinib-induced apoptosis of tumor cells differentially regulated by UBR5 and CDC73. In human triple-negative breast cancer (TNBC) patient specimens, a strong inverse correlation was observed between UBR5 and CDC73 protein levels, with reduced CDC73 expression at metastatic sites compared to primary lesions. Furthermore, a xenograft model of human TNBC recapitulated the metastatic properties and characteristics of the unique UBR5-CDC73 functional antagonism. This study reveals the novel and critical roles and intricate relationships of UBR5, CDC73 and p53 in postsurgical breast cancer metastasis and indicates the potential of targeting this pathway in cancer therapy.

OBJECTIVE: CDC73 has been reported to be upregulated in breast cancer. This study aimed to illuminate the underlying mechanism by which CDC73 mediates breast cancer.
METHODS: Here, a breast cancer tissue microarray and three breast cancer cell lines MDA-MB-231, BT-549 as well as MCF-7 were employed. Using RNAi method, we knocked down CDC73 and MAPK1 in breast cancer cells. CDC73 overexpression plasmids (LV-013) were generated through pMD2.G and pSPAX2 vectors. Cell events related to tumor development were analyzed through Celigo cell counting assay, a cell counting kit, wound healing assay, Transwell assay and flow cytometry analysis. The exploration on the underlying mechanism was based on PrimeView human gene expression array. Xenograft tumor models were constructed to visualize the effects of CDC73/MAPK2 on breast cancer progression.
RESULTS: CDC73 was abundantly expressed in breast cancer tissues and cell lines, and the expression of CDC73 was related to poor prognosis of patients. In breast cancer, CDC73 could promote the proliferation and migration of tumor cells, while disrupting apoptosis. Also, we found that CBL, an E3 ubiquitin ligase, could interact with CDC73 and promote MAPK1 ubiquitination and degradation of this protein. In addition, silencing MAPK1 led to a suppression of breast cancer cell growth in vitro and in vivo, and even abolished the promoting effects of CDC73 overexpression. We also found that mTOR pathway played a role in CDC73-mediated breast cancer. mTOR pathway inhibitor reversed cell phenotypes induced by CDC73 overexpression.
CONCLUSIONS: CDC73 promoted MAPK1 ubiquitination and degradation so that affected MAPK1 level and subsequently led to breast cancer progression, providing a novel therapeutic strategy to combat cancer.

Cells trigger the assembly of stress granules (SGs) under various stress conditions. Among the many proteins recruited to SGs are RNA-binding proteins and transcription regulators. Here, we report the translocation of human (h)Cdc73, a component of the PAF1 transcription complex, to cytosolic SGs in response to arsenic stress. The hCdc73 protein possesses a long intrinsically disordered region (IDR) from amino acids 256-416, the presence of which is required for the translocation of hCdc73 to cytosolic SGs. The purified hCdc73 IDR formed droplets in vitro, and the light-activated assembly of hCdc73-IDR-mCherry-CRY2 was verified. For translocation of hCdc73 to SGs, physical interactions with SG carrier proteins, such as FMR1, are also needed. Previously, we reported that the cytosolic hCdc73-eEF1Bγ complex controls the stability of p53 mRNA. Under arsenic stress, selective sequestration of cytosolic hCdc73, but not eEF1Bγ (EEF1G) or p53 (TP53) mRNA, was detected. As a result, a transient increase in p53 mRNA at the post-transcriptional level was observed. In conclusion, we propose that the availability of mRNAs for stress-responsive genes can be controlled by restraining their negative regulators within SGs.

BACKGROUND: Endoplasmic reticulum (ER) stress plays an important role in the occurrence and development of various liver diseases. However, there are no effective prevention and treatment strategies. We aimed to determine the role of heat shock factor 2 binding protein (HSF2BP) in ER stress.
METHODS: HSF2BP expression in mice and cultured hepatocytes was measured during ER stress induced by tunicamycin, and its importance in ER stress was evaluated in hepatocyte-specific HSF2BP transgenic (TG) and knockout (KO) mice. The effects and mechanisms of HSF2BP on ER stress were further probed in hepatic ischemia-reperfusion (I/R) injury.
RESULTS: HSF2BP expression was significantly upregulated during tunicamycin-induced ER stress in mice and cultured hepatocytes. Liver injury and ER stress were reduced in HSF2BP overexpressing mice after treating with tunicamycin, but were aggravated in HSF2BP knockout mice compared to the controls. In hepatic I/R injury, HSF2BP expression was significantly upregulated, and HSF2BP overexpressing mice had reduced liver injury and inflammation. These improvements were associated with ER stress inhibition. However, these results were reversed in hepatocyte-specific HSF2BP knockout mice. HSF2BP overexpression increased cytoplasmic CDC73 levels and inhibited the JNK signaling pathway. CDC73 knockdown using siRNA eliminated the protection exerted by HSF2BP overexpression in hypoxia/reoxygenation (H/R)-induced ER stress in hepatocytes.
CONCLUSIONS: HSF2BP is a previously uncharacterized regulatory factor in ER stress-likely acts by regulating CDC73 subcellular localization. The feasibility of HSF2BP-targeted treatment in ER stress-related liver disease deserves future research.

Parathyroid cancer (PC) is a rare endocrine neoplasm with high mortality. While surgery is the treatment for patients with the disease, recurrence rates are high, and patients usually succumb to severe hypercalcemia. There is no effective systemic therapy for the disease.
To investigate for novel genes causing parathyroid cancer.
We analyzed the germline DNA of 17 patients with \"sporadic\" PC and 3 with atypical parathyroid tumors (APTs) who did not have germline CDC73 or MEN1 pathogenic variants. Sequencing of available tumor tissue from 14 patients with PC and 2 with APT was also performed (including 2 patients with no available germline DNA). In addition, sporadic parathyroid adenomas from 74 patients were analyzed for FLCN variants.
We identified germline FLCN variants in 3 unrelated patients with PC. The 2 frameshift variants have been described in patients with Birt-Hogg-Dubé (BHD) syndrome, while the pathogenicity of the missense variant c.124G > C (p.G42R) has not been definitively established. Functional analysis of the missense variant showed a potential effect on posttranslational modification. All 3 patients with germline FLCN variants were noted to have renal cysts and 2 had lung cysts, features associated with BHD syndrome. Somatic FLCN variants were identified in tumors from 2 (1 APT) of 16 patients with PC/APT and in none of the 74 sporadic parathyroid adenomas. No second hits in FLCN were noted on sequencing; however, loss of heterozygosity at the locus was demonstrated in 2 of 3 patients with the identified germline FLCN variant.
The finding of FLCN variants associated with PC may provide the foundation for the development of therapy for this malignancy.

CDC73 alterations are associated with three main parathyroid lesions according to the World Health Organization (WHO) classification of tumors of the endocrine system. These include hyperparathyroidism-jaw tumor (HPT-JT) syndrome-associated adenomas, atypical parathyroid tumors (APTs), and parathyroid carcinomas (PCs). The loss of nuclear parafibromin expression, which serves as a surrogate marker for the underlying CDC73 alteration, encompasses these tumors under the term parafibromin-deficient parathyroid tumors. They have distinct morphologic features of more abundant eosinophilic cytoplasm with perinuclear clearing surrounding a large nucleus as well as prominent dilated branching \"hemangiopericytoma-like\" vasculature and a thick capsule as well as variably sized cystic spaces. These tumors include cases that show unequivocal histologic features fulfilling the criteria for PCs with growing data indicating a higher rate of recurrence or metastasis compared with parafibromin intact PCs. More importantly, the loss of parafibromin expression can be used in clinical practice to recognize APTs that fall short of a conclusive diagnosis of PCs, but clinically behave akin to them. Moreover, recognizing these tumors can lead to an underlying germline mutation and a diagnosis of HPT-JT, which impacts long-term treatment and surveillance for patients and close family.

BACKGROUND: Hyperparathyroidism-Jaw Tumor (HPT-JT) is caused by inactivating germline mutations of CDC73. This hereditary disease can present with a range of symptoms. Jaw ossifying fibroma (OF) is one of the most important clinical presentations, affecting 30% of HPT-JT patients. However, OF is easily confused with other fibro-osseous lesions (FOLs) of the jaw. The correct diagnosis of HPT-JT is a real challenge and must be confirmed by genetic testing.
METHODS: A female proband and her father suffered from multiple and recurrent FOLs in the jaw. Considering well demarcated margin and heterogeneous calcified substance lying in a variable density of fibrous stroma, we reached the diagnosis of jaw OF through radiologic and microscopic analyses. Additionally, the proband presented with chronic anemia resulting from menorrhagia, as well as renal mixed epithelial and stromal tumor (MEST). Two patients both presented with no evidence of Hyperparathyroidism (HPT). A germline start codon mutation (c.1A > G) of CDC73 was identified in them. Copy number loss at the CDC73 gene locus was verified in the jaw tumor sample of the proband.
CONCLUSIONS: Regardless of whether HPT manifestations are present, patients with heritable jaw OF may be at risk for HPT-JT. Genetic testing should be adopted to confirm the diagnosis. Early recognition of HPT-JT helps to better develop tailored treatment plans and surveillance programs.