Molecular Cancer Research最新文献

The malignant progression of human cancer is dictated by specific regulatory hubs coordinating multiple signaling modules. Identifying key oncogenic hubs of human cancers may lay the groundwork for developing breakthrough therapeutic strategies. Actin-like 6A (ACTL6A; also known as BAF53A) was originally identified as a chromatin remodeling factor involved in the transcriptional regulation of genes, especially in stem and progenitor cells. The preponderance of evidence revealed the overexpression of ACTL6A in most cancers and its crucial role in various malignant phenotypes, including cell-cycle progression, cancer stemness, epithelial-to-mesenchymal transition, redox and glucose metabolism, and DNA replication and repair. Interestingly, emerging data suggest that the oncogenic function of ACTL6A is mediated through diverse mechanisms beyond its canonical function in transcriptional regulation, including notably the stabilization of oncoproteins and stemness factors, such as YAP, VPS72, and MYC. In this review, we describe the isoforms and the putative functional domains of ACTL6A. We summarize the expression pattern and prognostic significance of ACTL6A in human cancers and the upstream regulatory mechanisms of its expression. We summarize recent progress in understanding the diverse pro-oncogenic functions of ACTL6A and emphasize its pleiotropic mechanisms of action as a regulatory hub of cancer stemness and progression. The review highlights the importance and the potential utilities of characterizing ACTL6A, which may imply molecularly informed diagnostics and therapeutics to improve the outcome of patients with cancer.

Cooperativity between mutant p53 and mutant KRAS, although recognized, is poorly understood. In pancreatic cancer, mutant p53 induces splicing factor hnRNPK, causing an isoform switch that produces overexpression of GTPase-activating protein 17 isoform 1 (GAP17-1). GAP17-1 is mislocalized in the cytosol instead of the membrane, owing to the insertion of exon 17 encoding a PPLP motif, thus allowing mutant KRAS to remain in the GTP-bound hyperactive state. However, the role of PPLP in influencing GAP17-1 mislocalization remains unclear. We show that Smad ubiquitination regulatory factor 2 (SMURF2), a known stabilizer of mutant KRAS, interacts with GAP17-1 via the PPLP motif and displaces it from the membrane, facilitating mutant p53-mediated mutant KRAS hyperactivation. We used cell lines with known KRAS and TP53 mutations, characterized SMURF2 expression in multiple pancreatic cancer mouse models (iKras*; iKras*, p53*, and p48-Cre; Kras*), and performed single-cell RNA sequencing and tissue microarray on preclinical and clinical samples. We found that SMURF2 silencing profoundly reduces the survival of mutant TP53; KRAS-driven cells. We show that a GAP17-1 AALA mutant does not bind to SMURF2, stays in the membrane, and keeps mutant KRAS in the GDP-bound state to inhibit downstream signaling. In mouse models, mutant KRAS and SMURF2 upregulation are correlated with pancreatic intraepithelial neoplasia and ductal adenocarcinoma lesions. Furthermore, patients with pancreatic ductal adenocarcinoma who received neoadjuvant therapy and express moderate-to-high SMURF2 show decreased overall survival (P = 0.04).

Implications: In TP53 and KRAS double-mutated pancreatic cancer, SMURF2-driven GAP17-1 membrane expulsion facilitates mutant p53-KRAS oncogenic synergy.

Activation of lineage-specific gene expression programs is mediated by the recruitment of lineage-specific transcription factors and their coactivators to chromatin. The lineage factor PAX8 drives essential gene expression in ovarian cancer cells and is required for tumor proliferation. However, the molecular details surrounding cofactor recruitment and specific activation of transcription by PAX8 remain unknown. Here, we identify an important functional interaction between PAX8 and the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We show that PAX8 can recruit SWI/SNF complexes to DNA, in which they function to open chromatin and facilitate the expression of PAX8 target genes. Genetic deletion of PAX8 results in loss of SWI/SNF from PAX8-bound enhancers, loss of expression of associated target genes, and reduced proliferation. These results can be phenocopied by pharmacological inhibition of SWI/SNF ATPase activity. These data indicate that PAX8 mediates the expression of an essential ovarian cancer proliferative program in part by the recruitment of the SWI/SNF complex, highlighting a novel vulnerability in PAX8-dependent ovarian cancer. Implications: PAX8 recruits SWI/SNF complexes to enhancers to mediate the expression of genes essential for ovarian cancer proliferation.

Approximately 97% of the human genome comprises noncoding sequences, with nearly half originating from transposable elements. Among these, retrotransposons represent a critical subclass that replicates via a "copy-and-paste" mechanism and significantly influences the regulation of host genomes. In both normal and pathologic contexts, retrotransposons contribute to a vast reservoir of regulatory elements that can modulate the expression of genes. If left unchecked, retrotransposons can substantially affect host transcriptional programs and genomic integrity. Therefore, various mechanisms, including epigenetic modifications, have been employed to mitigate their potentially deleterious effects. In diseases such as cancer, the epigenome is often significantly reprogrammed, which can lead to retrotransposon dysregulation. Drawing insights from recent studies conducted in human and murine cells, this review examines how retrotransposons expand the complexity of mammalian genomes, describes the impact of their epigenetic dysregulation on cancer development, and highlights the potential of targeting these sequences for therapeutic strategies.

The E3 ubiquitin ligase RING finger protein 6 (RNF6) has been widely recognized for its role in promoting tumorigenesis in multiple cancers. However, we found that it is downregulated in lung adenocarcinoma (LUAD), and the molecular rationale for this discrepancy remains unclear. In the present study, we find that RNF6, but not its ΔRING inactive form, inhibits LUAD cell proliferation and migration and sensitizes LUAD to chemotherapy. To understand the molecular mechanism, we utilize affinity purification/tandem mass spectrometry (MS-MS) to analyze RNF6-interacting proteins and find that cyclin D2 (CCND2), a key regulator of the G1-S transition in the cell cycle. RNF6 physically binds to CCND2 and mediates its K48-linked polyubiquitination and subsequent degradation. However, ΔRING RNF6 fails to mediate CCND2 for ubiquitination and degradation. Moreover, Thr280 is critically important for CCND2 stability. When Thr280 is mutated, CCND2 becomes more stable and less ubiquitinated by RNF6. Furthermore, RNF6 arrests LUAD cell cycle at the G1 phase by inhibiting the CCND2/phospho-Rb signaling pathway, which is consistent with decreased cell proliferation. Lastly, RNF6 curtails the growth of LUAD xenografts in vivo, associated with decreased CCND2 expression. Therefore, RNF6 is a novel E3 ligase of CCND2 and suppresses LUAD cell proliferation. Implications: This study reveals a novel regulation on cell-cycle transition in LUAD and suggests the RNF6/CCND2 axis may represent an alternative therapeutic target for the treatment of LUAD.

Triple-negative breast cancer (TNBC) presents significant clinical challenges because of its limited treatment options and aggressive behavior, often associated with poor prognosis. This study focuses on kindlin-2, an adapter protein, and its role in TNBC progression, particularly in hematopoiesis-mediated immune evasion. TNBC tumors expressing high levels of kindlin-2 induce a notable reshaping of hematopoiesis, promoting the expansion of myeloid cells in the bone marrow and spleen. This shift correlated with increased levels of neutrophils and monocytes in tumor-bearing mice over time. Conversely, genetic knockout (KO) of kindlin-2 mitigated this myeloid bias and fostered T-cell infiltration within the tumor microenvironment, indicating the pivotal role of kindlin-2 in immune modulation. Further investigations revealed that kindlin-2 deficiency led to reduced expression of PD-L1, a critical immune checkpoint inhibitor, in TNBC tumors. This molecular change sensitized kindlin-2-deficient tumors to host antitumor immune responses, resulting in enhanced tumor suppression in immunocompetent mouse models. Single-cell RNA sequencing, bulk RNA sequencing, and IHC data supported these findings by highlighting enriched immune-related pathways and increased infiltration of immune cells in kindlin-2-deficient tumors. Therapeutically, targeting PD-L1 in kindlin-2-expressing TNBC tumors effectively inhibited tumor growth, akin to the effects observed with genetic kindlin-2 KO or PD-L1 KO. Our data underscore kindlin-2 as a promising therapeutic target in combination with immune checkpoint blockade to bolster antitumor immunity and counteract resistance mechanisms typical of TNBC and other immune-evasive solid tumors. Implications: Kindlin-2 regulates tumor immune evasion through the systemic modulation of hematopoiesis and PD-L1 expression, which warrants therapeutic targeting of kindlin-2 in patients with TNBC.

Breast cancers of the Integrative Cluster 2 (IntClust-2) type, characterized by amplification of a small portion of chromosome 11, have a median survival of only 5 years. Several cancer-relevant genes occupy this portion of chromosome 11, and it is thought that overexpression of a combination of driver genes in this region is responsible for the poor outcome of women in this group. In this study, we used a gene editing method to knock out, one by one, each of the 198 genes that are located within the amplified region of chromosome 11 and determined how much each of these genes contributed to the survival of breast cancer cells. In addition to well-known drivers such as CCND1 and PAK1, we identified two different genes (SERPINH1 and P4HA3) that encode proteins involved in collagen synthesis and organization. Using both in vitro and in vivo functional analyses, we determined that P4HA3 and/or SERPINH1 provide a critical driver function for IntClust-2 basic processes, such as viability, proliferation, and migration. Inhibiting these enzymes via genetic or pharmacologic means reduced collagen synthesis and impeded oncogenic signaling transduction in cell culture models, and a small-molecule inhibitor of P4HA3 was effective in treating 11q13 tumor growth in an animal model. As collagen has a well-known association with tissue stiffness and aggressive forms of breast cancer, we believe that the two genes we identified provide an opportunity for a new therapeutic strategy in IntClust-2 breast cancers. Implications: Breast cancers with 11q13/14 chromosomal amplifications may be vulnerable to inhibitors of collagen synthesis.

EGFR is a highly expressed driver of many cancers, yet the utility of EGFR inhibitors (EGFRi) is limited to cancers that harbor sensitizing mutations in the EGFR gene because of dose-limiting toxicities. Rather than conventionally blocking the kinase activity of EGFR, we sought to reduce its transcription as an alternative approach to broaden the therapeutic window for EGFR inhibitors targeting wild-type (WT) or mutant EGFR. We found that YES1 is highly expressed in triple-negative breast cancer (TNBC) and drives cell growth by elevating EGFR levels. Mechanistically, YES1 stimulates EGFR expression by signaling to JNK and stabilizing the AP-1 transcription factor c-Jun. This effect extends beyond TNBC as YES1 also sustains EGFR expression in non-small cell lung cancer cells, including those that harbor the EGFR gatekeeper mutation T790M. The novel ability of YES1 to regulate the expression of WT and mutant EGFR mRNA and protein provides a potential therapeutic opportunity of utilizing YES1 blockade to broadly increase the efficacy of EGFR inhibitors. Indeed, we observed synergy within in vitro and in vivo models of TNBC and non-small cell lung cancer, even in the absence of EGFR-activating mutations. Together, these data provide a rationale for blocking YES1 activity as an approach for improving the efficacy of EGFR-targeting drugs in cancers that have generally been refractory to such inhibitors. Implications: YES1 sustains EGFR expression, revealing a therapeutic vulnerability for increasing the efficacy of EGFR inhibitors by lowering the threshold for efficacy in tumors driven by the WT or mutant receptor.

Kaposi sarcoma is a frequently aggressive malignancy caused by Kaposi sarcoma herpesvirus. People with immunodeficiencies, including human immunodeficiency virus (HIV), are at increased risk for developing Kaposi sarcoma, but our understanding of the contributions of the cellular genome to Kaposi sarcoma pathogenesis remains limited. To determine if there are cellular genetic alterations in Kaposi sarcoma that might provide biological or therapeutic insights, we performed whole-exome sequencing on 78 Kaposi sarcoma tumors and matched normal control skin from 59 adults with Kaposi sarcoma (46 with HIV-associated Kaposi sarcoma and 13 with HIV-negative Kaposi sarcoma) receiving treatment at the Uganda Cancer Institute in Kampala, Uganda. We found a very low mutational burden in all but one specimen (median = 11 mutations), which is the lowest number of mutations among all 33 tumor types in The Cancer Genome Atlas. No recurrent mutations were seen, and the most commonly affected oncogenic pathway was RTK/RAS. Mutational signatures included defective DNA mismatch repair and smoking. There was no evidence suggesting that multiple tumors from the same patient originated from the same original clone. The number of genome copy alterations per genome was higher in tumors from those without HIV infection and in tumors from participants with advanced stage disease, suggesting that lesions that take longer to develop may accumulate more alterations, although the number of alterations remains low compared with other cancers. Implications: Our findings indicate that the pathogenesis of Kaposi sarcoma differs from other malignancies and that the primary driver of carcinogenesis is Kaposi sarcoma-associated herpesvirus infection and expression of viral oncogenes, rather than clonal oncogenic transformation.

Metastasis accounts for the overwhelming majority of cancer deaths. In prostate cancer and many other solid tumors, progression to metastasis is associated with drastically reduced survival outcomes, yet the mechanisms behind this progression remain largely unknown. ATPase family AAA domain containing 2 (ATAD2) is an epigenetic reader of acetylated histones that is overexpressed in multiple cancer types and usually associated with poor patient outcomes. However, the functional role of ATAD2 in cancer progression and metastasis has been relatively understudied. Here, we employ genetically engineered mouse models of prostate cancer bone metastasis, as well as multiple independent human cohorts, to show that ATAD2 is highly enriched in bone metastasis compared with primary tumors and significantly associated with the development of metastasis. We show that ATAD2 expression is associated with MYC pathway activation in patient datasets and that, at least in a subset of tumors, MYC and ATAD2 can regulate each other's expression. Using functional studies on mouse bone metastatic cell lines and innovative organ-on-a-chip bone invasion assays, we establish a functional role for ATAD2 inhibition in reducing prostate cancer metastasis and growth in bone. Implications: Our study highlights ATAD2 as a driver of prostate cancer progression and metastasis and suggests it may constitute a promising novel therapeutic target.